Objectives: We sought to compare the histologic response, safety, and tolerability in Latino and non-Latino patients with hepatitis C virus (HCV) genotype 1 treated with peginterferon α-2a plus ribavirin (LATINO study). Methods: LATINO was a prospective, open-label, multicenter study that enrolled 269 Latinos and 300 non-Latinos receiving peginterferon α-2a 180 g/week and ribavirin 1,000/1,200 mg/day for 48 weeks. Liver biopsies were obtained within 18 months of baseline and at week 72. Improved or worsened liver fibrosis and necroinflammatory activity were assessed by the Ishak-modified histologic activity index scoring system. Efficacy and safety parameters were monitored during treatment and the 24-week follow-up period. Results: The primary study results published elsewhere showed a higher sustained virologic response (SVR) rate among non-Latinos than Latinos (49% vs. 34%; P0.001). Paired biopsy data were available for 157 Latinos and 201 non-Latinos. At baseline, more Latinos vs. non-Latinos had alanine aminotransferase (ALT) 3 × the upper limit of normal (20% vs. 18%) and cirrhosis (13% vs. 10%). Both groups experienced improvement in Ishak activity at week 72, although the improvement rates were higher in non-Latinos than Latinos (59% vs. 47%; P0.03). For both groups, more patients with SVR compared with non-responders had improved Ishak fibrosis scores. In both groups, baseline Ishak activity score (P0.0001 for both) was predictive of Ishak activity response. Additional predictors in Latinos were age (P0.0023), body mass index (BMI) (P0.068), baseline ALT quotient (P0.031), and baseline Ishak fibrosis scores (P0.021). There were no significant differences in steatosis changes between the two groups. Adverse events (AEs) and withdrawals due to AEs were more frequent in non-Latinos. Conclusions: Significant proportions of patients in both groups had histologic response to peginterferon α-2a plus ribavirin. However, histologic response was higher in non-Latinos than in Latinos regardless of virologic response. This study highlights the need for additional strategies to improve virologic response in Latinos.