BACKGROUND & AIMS: Interferon-free treatment options are rapidly evolving for patients with chronic hepatitis C virus (HCV) genotype 1b (GT1b) infection with cirrhosis and for non-responders to prior pegylated interferon and ribavirin therapy. We performed a phase 2b, open-label trial of the combination of ombitasvir (a NS5A replication complex inhibitor), paritaprevir, and ritonavir (an NS3/4A protease inhibitor)-an interferon-and ribavirin-free regimen-in difficult-to-treat patients, including prior null responders and patients with cirrhosis. METHODS: In an international study, 82 patients without cirrhosis (42 treatment-naive and 40 prior null responders) and 99 with cirrhosis (47 treatment-naive and 52 treatment-experienced with prior relapse or a null or partial response) with chronic HCV GT1b infection received ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) once daily for 12 weeks (without cirrhosis) or 24 weeks (with cirrhosis). The primary efficacy endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). RESULTS: In treatment-naive and null responder patients without cirrhosis, rates of SVR12 were 95.2% and 90.0%, respectively. In treatment-naive and treatment-experienced patients with cirrhosis, rates of SVR12 were 97.9% and 96.2%, respectively. No clinically meaningful differences in rates of SVR12 were observed between patients with or without cirrhosis. Virologic relapse occurred in 3 null responders without cirrhosis and 1 with cirrhosis; virologic breakthrough occurred in 1 null responder without cirrhosis. Common adverse events included headache, asthenia, pruritus, and diarrhea. One patient discontinued taking the drugs because of treatment-related adverse events. CONCLUSIONS: An interferon-and ribavirin-free regimen of ombitasvir, paritaprevir, and ritonavir, achieved high rates of SVR12 in patients with HCV GT1b infection with and without cirrhosis. This regimen was well tolerated and was associated with low rates of treatment discontinuation.