Randomized controlled trials of hepatitis C virus (HCV) therapy with pegylated interferon and ribavirin have demonstrated sustained viral response rates (SVRs) of 54%-63% (efficacy). Treatment results in clinical practice (effectiveness) may not be equivalent. The goal of this study was to assess the effectiveness of HCV treatment with pegylated interferon and ribavirin in a treatment-naïve, human immunodeficiency virus (HIV)-negative, United States urban population with many ethnic minority patients. We evaluated 2,370 outpatients for HCV therapy from 2001 to 2006 in the Faculty Practice of the Albert Einstein College of Medicine or the attending-supervised Montefiore Medical Center Liver Clinic. Care was supervised by one experienced physician under conditions of everyday clinical practice, and appropriate ancillary resources were made available to all patients. Two hundred fifty-five patients were treated with a mean age of 50 years (60% male, 40% female; 58% Hispanic, 20% African American, 9% Caucasian, 13% other; 68% genotype 1, the remainder genotypes 2 or 3). Patients had at least one liver biopsy. Intention-to-treat analysis (ITT) showed SVR in 14% of genotype 1 patients and 37% in genotype 2/3 patients (P < 0.001). SVR was significantly higher in faculty practice (27%) than in clinic patients (15%) by intention-to-treat (P = 0.01) but not per-protocol analysis (46% faculty practice, 34% clinic). 3.3% of 1,656 treatment-naïve, HIV antibody-negative individuals ultimately achieved SVR. Current hepatitis C therapies may sometimes be unavailable to, inappropriate for, and ineffective in United States urban patients. Treatment with pegylated interferon and ribavirin was less effective in this population than is implied by multinational phase III controlled trials. New strategies are needed to care for such patients.