This study aimed to estimate the prevalence and risk factors for hepatitis C virus (HCV) infection in Mexican Americans living in South Texas. We tested plasma for the presence of HCV antibody from the Cameron County Hispanic Cohort (CCHC), a randomized, population-based cohort in an economically disadvantaged Mexican American community on the United States/Mexico border with high rates of chronic disease. A weighted prevalence of HCV antibody of 2·3% [n = 1131, 95% confidence interval (CI) 1·2–3·4] was found. Participants with diabetes had low rates of HCV antibody (0·4%, 95% CI 0·0–0·9) and logistic regression revealed a statistically significant negative association between HCV and diabetes (OR 0·20, 95% CI 0·05–0·77) after adjusting for sociodemographic and clinical factors. This conflicts with reported positive associations of diabetes and HCV infection. No classic risk factors were identified, but important differences between genders emerged in analysis. This population-based study of HCV in Mexican Americans suggests that national studies do not adequately describe the epidemiology of HCV in this border community and that unique risk factors may be involved.