Genetic variation may explain the heterogeneity in the lipid response to dietary change. A systematic literature review found 79 articles on dietary intervention studies, 14 articles on observational studies, and 22 reviews on diet-gene interactions. The evidence suggests that variation within the genes for apolipoprotein (apo) AI, AIV, B and E may influence the lipid response to dietary change. This study assessed the influence of six polymorphisms within the genes for apo B, apo E and lipoprotein lipase (LPL) on the association between habitual diet and lipid levels in 239 healthy men and women (91 men and 148 women) aged 18-54 years, including 110 twin pairs, who were recruited for a population-based study of coronary heart disease (CHD) risk factors. Diet was assessed by a food frequency questionnaire, which was compared with 4-day weighed records in 41 men and 40 women aged 19-58 years. The nutrients of interest had either a correlation coefficient ≥0.5, ≥50/≤10% in the same/opposite third, a KW30.04. Genotypes were determined by the polymerase chain reaction and digestion with the appropriate enzyme. Significant diet-gene interactions were observed at each of the polymorphic sites, suggesting that genetic variation contributes to the framework within which diet, especially n-3 PUFAs, the P:S ratio and NSP can influence lipid levels. In particular, individuals with the apo B XbaI X+ allele, the apo B signal peptide insertion/deletion D allele, the apo &egr;4 allele, the LPL PvuII P- allele and the LPL S447X X allele may be at greater risk of developing CHD due to their poorer lipid profiles and/or poorer response to diet. At present, it is premature to recommend the use of genotyping in the design of therapeutic diets, however investigating diet-gene interactions will increase our knowledge of the mechanisms involved in the role of diet in reducing CHD risk.