To study the effects of reduced CD4 T cell activity on hepatitis C virus (HCV) genetic heterogeneity, HCV quasi-species complexity and diversification over time were analyzed for 56 human immunodeficiency virus-coinfected patients. Patients were selected retrospectively from the French Seroconverter Cohort (SEROCO) and the French Hemophilia Cohort (HEMOCO) for having stable CD4 cell counts for 3 years. HCV complexity was assessed by single-strand conformation polymorphism analysis of the envelope-coding region (HVR) and the core region at 2 time points 3 years apart. Increased HVR complexity was associated with higher CD4 cell count and HCV genotype 1 infection. Qualitative variation of HVR and core region was not related to CD4 cell count and depended on the initial complexity. Complexity of both regions remained unchanged over 3 years. Among these HCV-HIV-coinfected patients with stable CD4 cell counts, viral genotype and CD4 cell count may have influenced HVR complexity before their inclusion in the study but were not involved in HVR diversification during the 3-year follow-up period.