Candidate genes, including myxovirus resistance-1 (Mx1), protein kinase (PKR), transforming growth factor-beta1 (TGF-beta), interleukin-10 (IL-10), and interferon-gamma (IFN-gamma), were evaluated for associations with liver fibrosis in 374 treatment-naive patients with genotype-1 chronic HCV infection [194 Caucasian Americans (CAs) and 180 African Americans (AAs)], using a genetic haplotype approach. Among the 18 haplotypes that occurred with a frequency >or=5% in the cohort overall, the Mx1-(-123C)-(+6886A)-(+19820G(379V))-(+38645T) (abbreviated Mx1-CAGT), and PKR-(+110T)-(+7949G)-(+13846A)-(+22937T)-(+40342T) (abbreviated PKR-TGATT) haplotypes were independently associated with less severe hepatic fibrosis (Ishak >or= 3 versus <3). These associations persisted after adjustment for potential confounders such as alcohol use, sex, age (which is strongly correlated with the estimated duration of HCV infection [Spearman's correlation coefficient (r(s)) = 0.6)], and race (for Mx1-CAGT: OR = 0.33; 95% CI: 0.16-0.68; P = 0.0027; and for PKR-TGATT: OR = 0.56; 95% CI: 0.32-0.98; P = 0.0405). Population structure was evaluated using the structured association method using data from 161 ancestry-informative markers and did not affect our findings. We used an independent cohort of 34 AA and 160 CA in an attempt to validate our findings, although notable differences were found in the characteristics of the two patient groups. Although we observed a similar protective trend for the Mx1-CAGT haplotype in the validation set, the association was not statistically significant.