Both the human immunodeficiency (HIV) and hepatitis C (HCV) viruses have been associated with insulin resistance (IR). However, our understanding of the prevalence of IR, the underlying mechanisms and predisposing factors is limited, particularly among minority populations. We conducted a study of 333 Hispanic adults including: 76 HIV monoinfected, 62 HCV monoinfected, 97 HIV/HCV co-infected and 98 uninfected controls with a specific focus on HCV infection and liver injury as possible predictors of IR. IR was measured using the Quantitative Insulin Sensitivity Check Index (QUICKI). The majority (55–69%) of participants in all groups had QUICKI values <0.350. Body mass index was associated with IR in all groups. Triglycerides were associated with IR in the uninfected control group only (−1.83, SE = 0.58, P = 0.0022). HCV was associated with IR in participants infected with HIV (−0.012, SE = 0.0046, P = 0.010). Liver injury, as measured by score to assess liver injury (FIB-4) score, was significantly associated with IR independently of HCV infection (−0.0035, SE = 0.0016, P = 0.027). In the HIV/HCV co-infected group, treatment with nucleoside reverse-transcriptase (RT) inhibitors plus non-nucleoside RT inhibitors (−0.021, SE = 0.080, P = 0.048), but not protease inhibitors (−0.000042, SE = 0.0082, P = 0.96) was associated with IR. HCV infection and antiretroviral agents, including nucleoside RT inhibitor plus non-nucleoside RT inhibitor treatment are contributors to IR in HIV infection. Liver injury, as measured by the FIB-4 score, is a predictor of IR independently of HCV infection.