The purpose of this study was to systematically describe the neuropsychiatric side effects of treatment with interferon-alpha-2b (INF-alpha) and ribavirin in patients with chronic hepatitis C as well as to compare different instruments used to measure these side effects. Fifty-five patients with chronic hepatitis C were prospectively followed for 24 weeks and assessed with seven neuropsychiatric symptom measures and one quality of life scale. Of 42 patients treated with INF-alpha and ribavirin, 11 (26%) were receiving psychiatric treatment at baseline. They scored higher on all rating scales at baseline and became more symptomatic during treatment. Of the 31 patients (74%) not in psychiatric care at baseline, 15 (48%) required treatment for neuropsychiatric symptoms, and seven (23%) met criteria for major depression during INF-alpha therapy. The control group of 13 untreated subjects showed little change over the 24-week period. All symptom scales were highly intercorrelated, suggesting that use of one is sufficient for monitoring symptoms.