Insulin resistance affects sustained virological response (SVR) in chronic hepatitis C. To know whether adding metformin to standard antiviral treatment improves SVR, we conducted a prospective, multicentered, randomized, double-blinded, placebo-controlled trial in 19 Spanish hospitals, including 123 consecutive patients with genotype 1 chronic hepatitis C and insulin resistance. Patients were randomized to receive either metformin (arm A; n ؍ 59) or placebo (arm B; n ؍ 64) in addition to peginterferon alfa-2a (180 g/week) and ribavirin (1000-1200 mg/day). The primary end point was SVR, and secondary endpoints were viral clearance at weeks 12, 24, and 48, and changes in the homeostasis model assessment (HOMA) index over the first 24 weeks. There were no differences between arms at baseline. In the intent-to-treat analysis, SVR was observed in 53% versus 42% in arm A and arm B, respectively (P ؍ NS). In the subgroup analyses, SVR was higher in females (n ؍ 54) receiving metformin: arm A, 58% (15/26) versus 29% (8/28) arm B (P ؍ 0.03). In the per protocol analysis (PPA; n ؍ 101), SVR was 67% in arm A and 49% in arm B (P ؍ 0.06). Viral decline during the first 12 weeks was greater in females receiving metformin: ؊4.88 (1.18) versus ؊4.0 (1.44) (P ؍ 0.021), whereas no differences were seen in males. The triple therapy was well tolerated, but diarrhea was more often seen in arm A (34% versus 11%; P < 0.05). Conclusion: Adding metformin to peginterferon and ribavirin was safe and improved insulin sensitivity. Although the study failed to show a statistically significant difference between arms, it did show an improved SVR in females. (HEPATOLOGY 2009;50:1702-1708.) H epatitis C is a major healthcare problem, and current therapies have achieved sustained response in more than a half of infected patients. Factors associated with nonresponse are host-viral genotype 1, high viral load, advanced fibrosis, and insulin resistance. 1 Sustained virological response (SVR) decreases when insulin sensitivity is impaired. 1,2 Also, impaired fasting glucose has been independently associated with lower SVR rate. 3 Insulin resistance is thought to be promoted by hepatitis C virus (HCV) itself and, after clearance of the virus, insulin resistance improves concomitantly with the reduction in the risk of glucose abnormalities and diabetes. 1,3,4 HCV proteins lead to insulin resistance, promoting the degradation of insulin re-Abbreviations: HCV, hepatitis C virus; HOMA, homeostasis model assessment; IR, insulin resistance; PPA, per protocol analysis; PPAR-␥, peroxisome proliferatoractivated receptor-gamma; SD, standard deviation; SVR, sustained virological response.