This study compared the quality of life (QoL) of HIV-infected patients with and without hepatitis C and examined the sociodemographic, HIV-related and psychological symptoms associated with the QoL domains in patients with HIV/HCV co-infection. The sample consisted of 248 HIV/HCV coinfected patients (18-74 years, 81.5% male) and 482 patients only with HIV (24-78 years, 62.7% male). Participants completed the WHOQOL-HIV-Bref questionnaire and the Brief Symptom Inventory (BSI). The HIV/HCV co-infected patients reported significantly lower QoL in all domains, as well as significantly lower scores in 10 of the 17 specific facets. Overall, among the co-infected patients, male gender, employment, combination antiretroviral therapy use and fewer depressive and anxiety symptoms were significantly associated with higher QoL. Symptoms of psychological distress accounted for significant variability in the QoL scores of co-infected patients. These data reinforce the need for tailored interventions to improve the overall well-being of HIV/HCV co-infected patients.