Background: The incidence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is higher in men than in women. We examined whether endogenous sex hormone levels or hormone-related factors might affect the risk of HCC in men. Methods: Baseline blood samples were collected from 4841 male Taiwanese HBV carriers without diagnosed HCC from 1988 through 1992. Plasma testosterone and estradiol levels and genetic polymorphisms in the hormone-related factors cytochrome P450c17α (CYP17, A1 versus A2 alleles), steroid 5α-reductase type II (SRD5A2, valine [V] versus leucine [L] alleles), and androgen receptor (AR, number of CAG repeats) were assayed among 119 case patients who were diagnosed with HCC during 12 years of follow-up and 238 control subjects. All statistical tests were two-sided. Results: The risk of HCC increased with increasing concentrations of testosterone (odds ratio [OR]_{highest versus lowest tertile} = 2.97; 95% confidence interval [CI] = 1.54 to 5.70; P_trend <.001) and with increasing number of the V allele of the SRD5A2 V89L polymorphism (OR_{VV versus LL genotype} = 2.47; 95% CI = 1.21 to 5.03; P_trend = .011). Fewer AR gene CAG repeats (<23 repeats) were associated with a 1.64-fold (95% CI = 1.00 to 2.68) increased risk of HCC. Although the CYP17 genotype alone did not increase the risk of HCC, there was evidence of a gene–gene interaction, because the CYP17 A1 allele statistically significantly increased the risk of HCC in the presence of fewer AR gene CAG repeats (OR = 2.51; 95% CI = 1.06 to 5.94). We found a similar interaction between the SRD5A2 VV genotype and fewer AR gene CAG repeats (OR = 5.58; 95% CI = 1.86 to 16.71). Body mass index (BMI) modified the association of HCC with testosterone and SRD5A2 genotype; in men with low BMI, multivariate-adjusted ORs for the highest tertile of testosterone versus the lowest and the SRD5A2 VV genotype versus the LL genotype were 7.63 (95% CI = 2.13 to 27.27) and 8.64 (95% CI = 2.75 to 27.14), respectively. No clear associations were found between estradiol or testosterone-to-estradiol ratio and HCC. Conclusions: Pathways involving androgen signaling may affect the risk of HBV-related HCC among men.