OBJECTIVES: Chronic Hepatitis C virus (HCV) infection is one of the silent global epidemics with significant unmet need and disease burden. One of the major limitations of current treatments is the need for 12 or 6 months of Interferon based therapy, which has tolerability and toxicity issues for many patients. During last 2-3 years several new agents have been tested in clinic, which have shown promising results as non-interferon based therapy. Goal of this study was to review the clinical efficacy and safety profile of non-interferon based therapies for HCV treatment. METHODS: We searched the MEDLINE, and abstracts from AASLD and EASL until May 2011. Studies were selected for clinical trials on direct acting agents for HCV. Primary endpoints reviewed were Sustained Viral Response (SVR). Toxicity was evaluated as secondary endpoint. Aggregated data were further analyzed to understand comparative safety and efficacy. RESULTS: Until May 2011, results of five eligible HCV clinical trials for interferon free regimens were available. Overall, treatment with combination of protease and polymerase inhibitor showed dramatic viral load reduction after 2 weeks of treatment. The combination of PSI-7977 and PSI-938 showed 93% viral clearance after 14 days (n=16). The combination of RG7227 and RG7128 demonstrated 5.1 log reduction in viral load in treatment naive, and 4.9 log reduction in null responder patients after 14 days of treatment. The combination of BMS-790052 and BMS 650032 showed 36.3% 24 week SVR in null responder patients. One study evaluating VX-222 and Telaprevir combination was discontinued due to viral breakthrough. Several studies are currently on-going whose data would be available in 2011-2012. CONCLUSIONS: Non-interferon based therapies have shown impressive viral load reduction in short term studies. However, more data for SVR, viral breakthrough and resistance is needed to confirm their safe use in HCV infected population