For many conditions the overall impact of treatment on health related quality of life (HRQL) involves a tradeoff between improvement in the condition being treated and unwanted side effects. When the net HRQL result is too negative, patients have difficulty tolerating medication and may fail to adhere or discontinue treatment. OBJECTIVE: We investigated the association between reduced HRQL due to interferon treatment and premature treatment discontinuation for chronic hepatitis C. METHODS: A pooled secondary analysis of patients (n=1441) across three international, multicenter, open-label, randomized studies that compared peginterferon a-2a with interferon a-2a. Health-related quality of life was assessed using the SF-36 Health Survey. The Fatigue Severity Scale (FSS) was used to measure the impact of disabling fatigue. Logistic regression analysis was used to examine the association between changes in health-related quality of life and treatment discontinuation. RESULTS: Reduction from baseline in HRQL scores was a significant predictor of in-treatment SF-36 scores (P<0.001). The odds of discontinuing treatment early were were 48% higher in the quartile of patients with the greatest worsening of fatigue scores than in the lowest quartile. The odds ratios for treatment discontinuation among patients with worsening of SF-36 domain and summary scores ranged from 1.09 (physical function) to 3.56 (role limitations-emotional). CONCLUSION: The impact on health-related quality of life is an important consideration in optimizing treatment of patients with chronic hepatitis C. HRQL assessments during treatment may offer physicians a method for monitoring the risk of premature discontinuation.