The MONET study, comparing darunavir/ritonavir-based triple therapy and monotherapy, has found higher risk of failure in patients with positive HCV serology, but the effects of HCV co-infection on the efficacy of antiretroviral treatment have not been clearly established. A detailed MEDLINE search was conducted to identify cohort studies and clinical trials with published analyses of the efficacy of antiretroviral treatment by HCV co-infection. A meta-analysis of the clinical trials was conducted, with the standardized endpoint of HIV RNA < 50 copies/ml at week 48 (intent to treat, time to loss of virologic response algorithm). Twelve cohort studies, seven clinical trials in antiretroviral-naive patients and three in pretreated patients were identified. In the clinical trials, 637/5,408 (12%) patients had HIV/HCV co-infection by HCV antibody tests; this percentage was in the lower range of the percentage of HIV/HCV co-infected patients reported in cohort studies in North America and Europe (median 37%, range 9-64%). In the meta-analysis of the clinical trials, the mean percentage of patients achieving HIV RNA < 50 copies/ml at week 48 was 68.2% for HIV/HCV co-infected patients versus 80.4% for HIV mono-infected patients. The absolute difference in efficacy was 11.5% (95% CI: 7.7-15.3%; p < 0.001). However, a high proportion of endpoints in the time to loss of virologic response analysis were discontinuations of randomized treatment for adverse events or other reasons. The cause of the lower efficacy of antiretroviral treatment in HIV/HCV co-infected patients is unclear. The low percentage of HIV/HCV co-infected patients in this analysis, compared with published cohort studies, suggests that HCV co-infected patients are underrepresented in HIV clinical trials.