Summary. Self-efficacy or confidence in one’s ability to successfully engage in goal-directed behaviour has been shown to influence medication adherence across many chronic illnesses. In the present study, we investigated the psychometric properties of a self-efficacy instrument used during treatment for chronic hepatitis C viral infection (HCV). Baseline (n = 394) and treatment week 24 (n = 254) data from the prospective, longitudinal Viral Resistance to Antiviral Therapy of Chronic Hepatitis C study were examined. Baseline participants were randomly split into two equal-sized subsamples (S1 and S2). Initial exploratory and confirmatory factor analyses (EFA/CFA) were performed on S1, while S2 was used to validate the factor structure of the S1 results using CFA. An additional CFA was performed on the treatment week 24 participants. Convergent and discriminant validity were assessed by comparing the revised instrument with other psychosocial measures: depression, social support, quality of life and medication-taking behaviour. Our findings supported a reduced 17-item global measure of HCV treatment self-efficacy (HCV-TSE) with four underlying factors: patient communication self-efficacy, general physical coping self-efficacy, general psychological coping self-efficacy and adherence self-efficacy. The global score (0.92–0.94) and four factors (0.85–0.96) demonstrated good internal consistency. Correlations of convergent and discriminant validity yielded low to moderate associations with other measures of psychosocial functioning. The revised HCV-TSE instrument provides a reliable and valid global estimate of confidence in one’s ability to engage in and adhere to HCV antiviral treatment. The four-factor structure suggests different types of efficacy beliefs may function during HCV treatment and should be explored further in relation to clinical outcomes.