Because of increased mortality and reduced treatment response rates in subjects coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), understanding the selection pressures underlying the evolution of HCV is important for the development of strategies to control both viruses. We therefore investigated diversity of HCV in 11 HIV-HCV-coinfected subjects initiating highly active antiretroviral therapy (HAART). Distinct categories of HCV virologic response to suppression of HIV were identified. The diversity of quasi species at several genomic regions was characterized over the course of a 48-week period. Consensus data suggested a shift in the virus population at all loci except the 5' untranslated region (UTR) after initiation of HAART. Intrasubject genetic distance and entropy were highest in hypervariable region (HVR)-1. In contrast, variation in the 5' UTR was limited. Positive immune selection pressure directed against HVR-1, but not other protein-coding regions, was also detected. These data suggest that there are several mechanisms by which suppression of HIV replication and a reconstituted immune system influence diversity of HCV in HIV-HCV-coinfected subjects.