BACKGROUND: Several studies have demonstrated the negative impact of chronic hepatitis C (CHC) and respective treatments on patient health-related quality of life. Studies suggest PEGASYS provides an improved sustained virological response compared with interferon (IFN) monotherapy (30-39% vs 10-19%) and may provide safety, quality of life (QoL), and work productivity benefits compared with standard interferon/ribavirin (IFN/RBV, REBETRON™) combination therapy. OBJECTIVE: To compare the safety and tolerability of treatment with PEGASYS vs REBETRON in previously untreated patients with chronic hepatitis C (CHC). METHODS: A 72-week, multicenter study randomized 412 patients to PEGASYS 180 µg qw or REBETRON (IFN -2b 3 MIU tiw + RBV 1000-1200 mg qd). Tolerability was assessed by the Hepatitis Quality of Life Questionnaire (HQLQ, assessed at weeks 4, 12, 24, 48, 60, and 72; SF-36 plus 4 Hepatitis-specific domains) and the Work Productivity and Activity Impairment (WPAI) instrument. RESULTS: After 12 weeks of treatment, HCV-RNA was negative in 46.8% of PEGASYS and 50.3% of REBETRON patients. Patients on PEGASYS showed a clinically significant difference compared to REBETRON in several AEs: anemia (2.0% vs 32.4%), dyspnea (9.5% vs 18.1%), pruritus (6.7% vs 17.5%). At weeks 4 and 12, patients on PEGASYS compared to REBETRON had significantly better work productivity (Estimated Wkly Work Productivity Lost: $32.10, PEGASYS; $86.60, REBETRON) in 7 of 7 domains. Week 4 and 12 HQLQ assessments indicated patients on PEGASYS vs those on REBETRON had clinically and statistically better QoL scores in 8 of 8 SF-36 domains, both physical and mental summary scores, and 4 CHC-specific domains (P<0.05). CONCLUSIONS: The 12-week data demonstrate that patients treated with PEGASYS had a superior tolerance to therapy, were more productive as measured by the WPAI, and had better health related quality of life profiles compared with patients treated with REBETRON, while maintaining similar virological response.