To determine the influence of patient religiosity on the outcome of treatment of hepatitis C infection, a prospective, blinded, cohort study was performed on hepatitis C-infected patients categorized as 'higher religiosity' and 'lower religiosity' based on responses to a religiosity questionnaire. Comparisons were made between high and low religiosity patients on demographics, pre-treatment laboratory values, and response to treatment. Eighty-seven patients with complete questionnaires were placed in either higher (38) or lower (49) religiosity cohort. The patients (60% female) were ethnically diverse: African-American 39%; Hispanic 31%; white 29%. African-American race (P = 0.001) and female gender (P = 0.026) were associated with higher religiosity. The frequency of being offered treatment, accepting treatment, and completing treatment was similar in both religiosity cohorts (P = 0.234, 0.809, 0.367). Fifty-six patients completed the 24- or 48-week treatment with peginterferon and ribavirin. Depression was more frequent in the low religiosity group (38.2% vs. 4.6%, P = 0.005). Sustained viral response rate at 3-6-month post-therapy was similar in the higher (50%) and lower (57.6%) religiosity cohorts (P = 0.580; n = 55). Logistic regression modeling revealed that males having higher religiosity gave greater odds of SVR than those with lower religiosity (OR 21.3; 95% CI 1.1-403.9). The level of religiosity did not affect the decision to begin treatment for chronic HCV infection and was not associated with a better treatment outcome. A higher level of religiosity was associated with less depression among patients.