Low adherence and toxicities among HIV-positive patients starting highly active antiretroviral therapy (HAART) can lead to discontinuation of therapy and treatment failure. Little is known about hepatitis C (HCV) status and discontinuation of HAART. Poisson regression was used to determine factors related to discontinuation of any part of an initial HAART regimen due to treatment failure (TF) or toxicities and patient/physician choice (TOX), and to investigate the relationship between HCV and discontinuation of a HAART regimen in 1198 patients staring HAART after 1999 from the EuroSIDA study. At 1 year after starting HAART, 70% of patients remained on their original regimen, 24% had changed, and 6% were off all treatment. The most frequent reason for discontinuation was toxicities (30.4%). There was no change over time in the proportion of patients discontinuing after stratification by reason for discontinuation (p = 0.18). Of patients 190 stopped at least one antiretroviral drug used in their initial HAART regimen due to toxicities; the toxicity reported did not vary according to HCV status (p = 0.90). Anti-HCV seropositive patients had a higher incidence of discontinuation due to TOX (IRR 1.46, 95% CI 1.13-1.88, p = 0.0042) compared to patients without HCV. Patients with HCV were more likely to discontinue all or part of their HAART regimens due to toxicity or patient/physician choice. Managing adverse events must remain a key intervention in maintaining HAART. There is a need for further studies to describe the relationship between HCV, specific antiretrovirals, and different treatment strategies.