Clinical and epidemiological studies support a strong association between chronic inflammation and cancer. Inflammatory related cytokines, such as IL-1£\, IL-1RN, IL-1£], IL-4, IL-6, IL-8, IL-10, TNF-£\ and TGF£]-1, might play important role in carcinogenesis of oral squamous cell carcinoma (OSCC). Two case-control studies were carried out to evaluate the association of 16 various polymorphisms of 9 inflammatory-related genes with the risk for OSCC and the risk for betel quid (BQ)-related oral precancer lesions (OPL) and BQ-related OSCC. Then the association between various IL-1B C-511T/T-31C haplotypes with plasma levels of IL-1£] was evaluated. One case-contol study included 363 OSCC case patients and 487 healthy controls as well as the other case-control study included 227 BQ-related OSCC cases, 116 BQ-related OPL patients and 209 BQ-related controls. All subjects were recruited and genotyped by use of the PCR-RFLP techniques or TaqMan real-time PCR method from November 2003 and May 2007 at Kaohsiung Veterans General Hospital. Then, 9 OSCC case patients, 9 OPL patients, and 9 controls were selected and matched on sex, age as well as the quantity of BQ-chewing, alcohol drinking, and cigarette smoking for evaluation of plasma levels of IL-1£] by use of ELISA. In the single locus analysis, the variant genotype of RP1RP2 or RP2RP2 (VS. RP1RP1) of IL-4 intron 3 VNTR (AOR = 0.67, 95% CI = 0.45-0.99; AOR = 0.65, 95% CI = 0.45-0.95), TA or AA (VS. TT) genotype of IL-8 T-251A (AOR = 1.55, 95% CI = 1.05-2.30; AOR = 2.50, 95% CI = 1.46-4.27), TT (VS. CC) genotype of IL-8 C+781T (AOR = 2.01; 95% CI = 1.11-3.63), and GA combined with AA (VS. GG) genotype of TNFA G-308A (AOR = 0.40; 95% CI = 0.25-0.66) were associated with risk of OSCC, as compare with those genotypes of healthy controls. However, CC (VS. TT) genotype of IL-10 T-819C (AOR = 0.24, 95% CI = 0.08-0.74) and CC (VS. AA) genotype of IL-10 A-592C (AOR = 0.25, 95% CI = 0.08-0.79) were significantly associated with reduced risk of BQ-related OPL, as compared with those genotypes of BQ controls. In addition, the variant genotype of 2/2 or 1/2 (VS. 1/1) of IL-1RN intron2 VNTR (AOR = 0.11, 95% CI = 0.01-0.97; AOR = 0.48, 95% CI = 0.27-0.87), TC (VS TT) genotype of IL-1B T-31C (AOR = 1.82, 95% CI = 1.14-2.92), AA (VS. TT) genotype of IL-8 T-251A (AOR = 1.92, 95% CI = 1.01-3.66), GG (VS. TT) genotype of IL-8 T+396G (AOR = 2.18; 95% CI = 1.12-4.21), and GA combined with AA (VS. GG) genotype of TNFA G-308A (AOR = 0.46, 95% CI = 0.27-0.79) were significantly related with risk of BQ-related OSCC, as compared with BQ controls. Moreover, CC (VS. TT) genotype of IL-10 T-819C (AOR = 3.33, 95% CI = 1.07-10.42) was associated with increased risk of BQ-related OSCC, as compared with those genotypes of BQ-related OPL. In the haplotype analysis, -590C/RP2 (VS. -590T/RP1) haplotype of IL-4 (AOR = 0.69; 95% CI = 0.49-0.98) and -251A/+781T (VS. -251T/+781C) haplotype of IL-8 (AOR = 1.57, 95% CI = 1.19-2.06) were related with risk of OSCC, as compared with those haplotypes of healthy controls. However, -511C/-31C (VS. -511C/-31T) haplotype of IL-1B (AOR = 0.00, 95% CI = 0.00-0.01) and -1082A/-819C/-592C (VS. -1082A/-819T/-592A) haplotype of IL-10 (AOR = 0.66, 95% CI = 0.44-0.98) were strongly associated with reduced risk of BQ-related OPL, as compared with those genotypes BQ controls. In addition, -889C/2/-511C/-31T or -889T/1/-511C/-31T or -889T/1/-511T/-31C (VS. -889C/1/-511C/-31T) haplotypes of IL-1 family genes (AOR = 0.47, 95% CI = 0.26-0.87; AOR = 0.31, 95% CI = 0.13-0.73; AOR = 3.26; 95% CI = 1.34-7.93) were associated with risk of BQ-related OSCC, as compared with those genotypes of BQ controls. On the contrary, -511T/-31T (VS. -511C/-31T) haplotype of IL-1B (AOR = 0.34, 95% CI = 0.12-0.97) and -889T/1/-511C/-31T (VS. -889C/1/-511C/-31T) haplotype of IL-1 family genes (AOR = 0.27, 95% CI = 0.10-0.71) were associated with reduced risk of BQ-related OSCC, as compared with those haplotypes of BQ-related OPL. Finally, in the stratification analysis, the combined effects of three genes (IL-8 T-251A, IL-4 intron 3 VNTR and TNFA G-308A) had a significantly increased risk of OSCC among male, older group (¡Ö50 years old), Fukienece combined with Aborigine population, never-BQ chewers, never as well as heavy smokers, or light and heavy drinkers, compared with healthy controls. The results suggested that gene-environment combined effect were associated with the risk of OSCC. In ELISA assay, plasma IL-1£] levels in BQ-related OSCC and OPL were found significantly higher than those in haplotypes for IL-1B -511T/-31C and IL-1B -511T/-31T compared with the combined effects of IL-1B -511C/-31C and IL-1B -511C/-31T. In conclusion, polymorphisms of IL-1RN, IL-4 and TNFA were associated with the decreased risk of OSCC or BQ-related OPL, but IL-8 was with increased risk of OSCC or BQ-related OPL. Furthermore, polymorphisms of IL-1B and IL-10 had contrary effect between BQ-related OSCC and OPL. Additionally, plasma levels of IL-1£] was correlated with various IL-1B C-511T/T-31C haplotypes but not with correlated with the status of disease.