Chronic hepatitis C infection frequently coexists with human immunodeficiency virus (HIV) and together are associated with increased hepatic steatosis. Steatosis is a risk factor for progression of liver disease and may persist despite a sustained virologic response to hepatitis C treatment. Therefore, therapies to target hepatic steatosis are important for individuals with HIV and hepatitis C virus (HCV) coinfection. We completed a 48-week, randomized, double-blind, placebo-controlled trial of pioglitazone (45 mg/day) in 13 subjects with HIV/HCV coinfection. The primary outcome variable was hepatic fat content, measured by magnetic resonance spectroscopy (MRS) imaging. Individuals randomized to pioglitazone had a significant decrease in hepatic fat content measured by MRS from baseline (15.1 ± 7.0%) to week 48 (7.6 ± 3.9%), with a mean difference of -7.4% (p = 0.02, n = 5). There was no significant change in hepatic fat content with placebo. Glycemic control as measured by oral glucose challenge improved significantly with pioglitazone (p = 0.047). Though not statistically significant, there were trends toward improved alanine aminotransferase (ALT) and histopathologic grade of steatosis in subjects who received pioglitazone. Pioglitazone was well tolerated and no one discontinued due to side effects. This study demonstrates that 48 weeks of pioglitazone therapy, and not placebo, results in significant reductions in hepatic fat content as measured by MRS in subjects with HIV and HCV coinfection and hepatic steatosis. This small study shows that pioglitazone helps ameliorate steatosis in the context of HIV/HCV coinfection.