To determine the rates of patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) who discontinued therapy as a result of protease inhibitor (PI)-related hepatotoxicity, a retrospective review was conducted. Baseline CD4 counts, plasma HIV RNA levels, and duration of therapy were comparable between single- and dual-PI-treated subjects and between subjects receiving ritonavir-containing therapy and those receiving ritonavir-sparing therapy. The proportions of patients with elevations in alanine aminotransferase level to > or =5 times the upper limit of normal (19% versus 26%) and hyperbilirubinemia (30% versus 38%) were similar between the dual-PI (n=27) and single-PI treatment groups (n=39), respectively. No difference in these characteristics was observed between ritonavir-containing (n=34) and ritonavir-sparing (n=32) treatment arms. Rates of treatment discontinuation due to hepatotoxicity were similar for single-PI and dual-PI therapy and for ritonavir-containing and ritonavir-sparing regimens. Dual-PI therapy and inclusion of ritonavir do not seem to increase the rates of hepatotoxicity in PI-treated, HIV-HCV coinfected subjects.