HIV and HCV infections are both characterized by increased oxidative stress. Information on the magnitude of this increase and its consequences in HIV/HCV co-infection and viral replication is limited. We investigated the relationship between oxidative stress and HIV-progression in HIV/HCV co-infected and HIV mono-infected adults. 106 HIV/HCV co-infected and 115 HIV mono-infected participants provided demographic information and blood to determine 8-oxo-dG and percent oxidized glutathione. HIV/HCV co-infected subjects had higher percent oxidized glutathione, higher HIV viral load, lower mtDNA copies and higher liver fibrosis than mono-infected subjects. In a small sample of HIV/HCV co-infected participants with liver biopsy, 8-oxo-dG was significantly lower in participants with low fibrosis scores than those with high fibrosis scores, and the grade of inflammation was strongly associated with oxidized glutathione. HIV/HCV co-infection seems to diminish the capacity of the antioxidant system to control oxidative stress, and increases HIV replication.