Mericitabine is a nucleoside analog polymerase inhibitor of hepatitis C virus (HCV). Treatment‐naïve HCV genotype 1 or 4 patients were randomized to double‐blind treatment with oral mericitabine at a dosage of 500 mg twice‐daily (BID) for 12 weeks (A), 1,000 mg BID for 8 (B) or 12 weeks (C and D), or placebo BID for 12 weeks (E). All patients received pegylated interferon alpha‐2a (Peg‐IFNα‐2a; 40 kD)/ribavirin (RBV) at standard doses for 24 or 48 weeks during and after mericitabine/placebo therapy. Patients in arms A‐C who maintained a virologic response (VR) (HCV RNA <15 IU/mL) from weeks 4 to 22 stopped all treatment at week 24; all other patients (arms A‐E) continued Peg‐IFNα‐2a/RBV to complete 48 weeks. The primary outcome was sustained VR (SVR) (HCV RNA <15 IU/mL after 24 weeks of untreated follow‐up; SVR‐24). VR rates were higher in arms A‐D than in arm E at weeks 4 and 12 overall, in patients with and without cirrhosis and in patients with CC and non‐CC IL28B genotypes. However, the overall SVR‐24 rate in arms D (50.6%) and E (placebo, 51.2%) was similar and those in the response‐guided therapy arms A, B, and C were lower (48.8%, 42.0%, and 32.9%, respectively). No viral breakthrough or mericitabine‐resistance mutations (S282T) were observed during mericitabine therapy. Conclusion: Treatment with mericitabine plus Peg‐IFNα‐2a/RBV for 8 or 12 weeks provided potent suppression of HCV RNA, was well tolerated, and did not select resistant variants, but did not increase SVR rates, compared to placebo. IFN‐free and IFN‐containing trials of mericitabine of longer treatment duration are ongoing. (HEPATOLOGY 2013;58:524–537)