Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection is an important and frequent scenario, predominantly in injecting drug users (IDUs). The present study evaluated morbidity and mortality variation in HIV-infected patients with and without HCV co-infection. Co-infection prevalence was determined in 356 HIV-infected persons. Their clinical manifestations, laboratory findings, risk factors, HIV therapies, and mortality rates were evaluated. The prevalence of HCV was 54% in the overall group and 81% in IDUs, with a predominance of HCV genotype 1. Mortality rates were similar in patients with and without co-infection; however, co-infected patients had significantly higher liver damage as a cause of mortality when compared with those who were not co-infected. The high prevalence of HCV and an emerging mortality from liver diseases showed the significance of this co-infection in the HIV epidemic. Primary and secondary prevention are necessary to reduce the expanding impact of HCV infection in HIV patients.