Background. Sustained virological response (SVR) after therapy with interferon plus ribavirin reduces liver-related complications and mortality in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). We assessed the effect of SVR on HIV progression and mortality not related to liver disease. Methods. An observational cohort study including consecutive HIV/HCV-coinfected patients treated with interferon plus ribavirin between 2000 and 2008 in 19 centers in Spain. Results. Of 1599 patients, 626 (39%) had an SVR. After a median follow-up of approximately 5 years, we confirmed that failure to achieve an SVR was associated with an increased risk of liver-related events and liver-related death. We also observed higher rates of the following events in nonresponders than in responders: AIDS-defining conditions (rate per 100 person years, 0.84 95% confidence interval (CI), .59–1.10 vs 0.29 .10–.48; P = .003), non—liver-related deaths (0.65 .42–.87 vs 0.16 .02–.30; P = .002), and non—liver-related, non—AIDS-related deaths (0.55 .34–.75 vs 0.16 .02–.30; P = .002). Cox regression analysis showed that the adjusted hazard ratios of new AIDS-defining conditions, non—liver-related deaths, and non—liver-related, non—AIDS-related deaths for nonresponders compared with responders were 1.90 (95% CI, .89–4.10; P = .095), 3.19 (1.21–8.40; P = .019), and 2.85 (1.07–7.60; P = .036), respectively. Conclusions. Our findings suggest that eradication of HCV after therapy with interferon plus ribavirin in HIV/HCV-coinfected patients is associated not only with a reduction in liver-related events but also with a reduction in HIV progression and mortality not related to liver disease.