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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%). The incidence of any discontinuation was significantly lower after 1999 compared to before [incidence rate ratio (IRR) 0.43; 95% CI 0.35–0.53, p < 0.0001], this pattern was most marked for toxicities (IRR 0.28; 95% CI 0.20–0.39, p < 0.0001) and patient/physician choice (IRR 0.49; 95% CI 0.33–0.73, p < 0.0001). Patients with HCV 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.