Background: We aimed to investigate the associations between androgen status and markers of liver disease severity and to determine the effect of interferon-alpha (IFN-alpha) treatment on sex hormone levels in the context of hepatitis C infection.Methods: We audited liver biopsy and sex hormone data from 35 men with chronic hepatitis C and a separate group of 11 men with hepatitis C who received IFN-alpha treatment at Fremantle Hospital.Results: We found that men with low fibrosis scores (0-2) on the modified Knodell histological activity index were more likely to have lower sex hormone-binding globulin (SHBG) levels (38.2 +/- 13.2 vs 66.6 +/- 43.3 nmol/L, P < 0.001) and higher free testosterone levels (380.4 +/- 102.0 vs 255.9 +/- 83.0 pmol/L, P = 0.01) than those with higher fibrosis scores (3-6). SHBG directly correlated with fibrosis scores (r = 0.37, P = 0.032). Free testosterone levels inversely correlated with liver fibrosis scores (r = -0.43, P = 0.011). A transient reduction in total testosterone of 5.7 +/- 4.2 nmol/L (P = 0.014) occurred within the first 6 months of IFN-alpha therapy although free testosterone was unaffected.Conclusion: More severe liver disease was associated with lower free testosterone and higher SHBG. IFN-alpha therapy reduced total testosterone but not to hypogonadal levels, with no decline in free testosterone. These data suggest that liver disease in hepatitis C infection modulates androgen status indirectly via increased SHBG. Screening for androgen deficiency in the context of hepatitis C infection should selectively target men with more severe liver disease or documented higher grade fibrosis.