Objectives: To demonstrate the effectiveness of hepatitis C virus (HCV) therapy and survival benefit from sustained virologic remission (SVR) in a safety net hospital population with limited resources. Design and setting: We conducted a retrospective cross-sectional study at an urban safety-net hospital in the U.S. Participants and intervention: 242 patients receiving standard HCV therapy between 2001 and 2006. Primary and secondary outcome measures: Response rates, including sustained virologic response (SVR), were recorded for each patient. Univariate and multivariate analyses were performed to identify predictors of SVR and 5 year survival. Results: A total of 242 eligible patients were treated. Treatment was completed in 197 (81%) patients, with 43 patients discontinuing therapy early – 32 due to adverse events and 11 due to non-compliance. Complications on treatment were frequent, including 3 deaths. SVR was achieved in 83 patients (34%). On multivariate analysis, independent predictors of a decreased likelihood of achieving SVR included African American race (OR 0.20, 95% CI 0.07 – 0.54), genotype 1 HCV infection (OR 0.25, 95% CI 0.13 – 0.50) and the presence of cirrhosis (OR 0.26, 95% CI 0.12 – 0.58). Survival was 98% in those achieving SVR (median follow-up 72 months) and 71% in non-responders and those discontinuing therapy (n = 91, median known follow-up 65 and 36 months respectively). On multivariate analysis, the only independent predictor of improved survival was SVR (HR 0.12, 95% CI 0.03 – 0.52). Both cirrhosis and hypoalbuminemia were independent predictors of increased mortality. Conclusions: HCV therapy can be effective despite limited resources. Survival is improved in those achieving SVR. Treatment before histologic cirrhosis develops, in combination with careful selection, may improve long-term outcomes without compromising other health care endeavors in safety net hospitals and areas with financial limitations.