We have established a cohort of natural viral suppressors (NVS) who can suppress HIV-1 replication to less than 400 copies/ml in the absence of therapy (similar to Elite Controllers/Elite Suppressors). Of the 59 patients currently in the NVS cohort, 45.8% have chronic hepatitis C virus (HCV) infection, thereby presenting a unique opportunity to study immune activation and the interaction between HCV and HIV. NVS with chronic HCV infection had elevated levels of immune activation (CD38-positive HLA-DR-positive CD8 cells) compared to NVS without chronic HCV (P = 0.004). The increased levels of immune activation were not associated with sex, HLA B57 status, or injection drug use use. NVS patients with chronic HCV had lower mean CD4 cell counts, CD4 percentage, and CD4/CD8 ratios than NVS without chronic HCV infection (P = 0.038, P = 0.008, and P = 0.048, respectively). The difference in CD4 cell count appeared to occur early in HIV infection with no difference observed in CD4 slopes between groups. Among all NVS, there was a direct correlation between mean CD4 cell count, mean CD4 percentage, and mean CD4/CD8 ratio with percentage of CD38 HLA-DR CD8 cells (P = 0.0018; P = 0.0069; and P = 0.0014, respectively). This study suggests a relationship between HCV infection, immune activation, and CD4 cell counts in the NVS, with chronic HCV infection associated with lower CD4 cell counts and higher levels of immune activation. Further studies are needed to determine if successful HCV treatment lowers immune activation levels and/or increases CD4 cell counts in these patients.