BACKGROUND Reports are mixed as to whether highly active antiretroviral therapy (HAART) increases liver transaminase levels or hepatitis C virus (HCV) titers in HIV/HCV-coinfected individuals. It is hypothesized that increases in HCV RNA titers may result from changes in endogenous interferon-alpha (IFN-alpha) production. METHODS HIV/HCV-coinfected patients receiving HAART were tested at baseline, 1, 2, 3, 6, and 9 months for liver transaminase levels, HIV and HCV viral loads, and IFN-alpha. Linear regression analysis was used to determine the effect of HAART on liver transaminase levels, HCV viral load, and IFN-alpha. RESULTS Initiating HAART did not increase liver transaminase levels in majority of cases. In patients (n = 30) with baseline HIV titer >10,000 copies/mL, HCV titers increased 0.69 log10 and IFN-alpha decreased -0.96 log10 during HAART, in association with a > or =0.5 log10 decrease in HIV titer. As HIV titers reached their nadir approximately 4 months after initiation of HAART, HCV titers remained 0.54 log10 and IFN-alpha -0.71 log10 above and below baseline levels, respectively. HCV titers and IFN-alpha levels did not change from baseline in patients with baseline HIV titer < or =10,000 copies/mL. CONCLUSIONS Coinfected patients did not have evidence of hepatoxicity HAART. In patients with baseline HIV titer >10,000 copies/mL, suppression of HIV replication by HAART was associated with an increase in HCV titer and a decrease in endogenous IFN-alpha levels.