AIM To evaluate magnitude/direction of changes in peripheral lipid profiles in patients undergoing direct acting therapy for hepatitis C by genotype. METHODS Mono-infected patients with hepatitis C were treated with guideline-based DAAs at a university-based liver clinic. Patient characteristics and laboratory values were collected before and after the treatment period. Baseline demographics included age, ethnicity, hypertension, diabetes, hyperlipidemia, treatment regimen, and fibrosis stage. Total cholesterol (TCHOL), high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides (TG), and liver function tests were measured prior to treatment and ETR. Changes in lipid and liver function were evaluated by subgroups with respect to genotype. Mean differences were calculated for each lipid profile and liver function component (direction/magnitude). The mean differences in lipid profiles were then compared between genotypes for differences in direction/magnitude. Lipid profile and liver function changes were evaluated with Levene's test and student's t test. Mean differences in lipid profiles were compared between genotypes using ANOVA, post hoc analysis via the Bonferroni correction or Dunnett T3. RESULTS Three hundred and seventy five patients enrolled with 321 (85.6%) achieving sustained-viral response at 12 wk. 72.3% were genotype 1 (GT1), 18.1% genotype 2 (GT2), 9.7% genotype 3 (GT3). Baseline demographics were similar. Significant change in lipid profiles were seen with GT1 and GT3 (Delta GT1, p and Delta GT3, p), with TCHOL increasing (+ 5.3, P = 0.005 and + 16.1, P < 0.001), HDL increasing (+ 12.5, P < 0.001 and + 7.9, P = 0.038), LDL increasing (+ 7.4, P = 0.058 and + 12.5, P < 0.001), and TG decreasing (-5.9, P = 0.044 and -9.80 P = 0.067). Among genotypes (Delta GT1 v.Delta GT2 v.Delta GT3, ANOVA), significant mean differences were seen with TCHOL (+ 5.3 v. + 0.1 v. + 16.1, P = 0.017) and HDL (+ 12.3 v. + 2 v. + 7.9, P = 0.040). Post-hoc, GT3 was associated with a greater increase in TCHOL than GT1 and GT2 (P = 0.028 and P = 0.019). CONCLUSION Successful DAA therapy results in increases in TCHOL, LDL, and HDL and decrease in TG, particularly in GT1/ GT3. Changes are most pronounced in GT3.