One hundred fifty patients with sustained virologic response (SVR) after treatment of chronic hepatitis C were enrolled in a long‐term clinical follow‐up study; patients were followed for 5 years for liver‐related outcomes and evidence of biochemical or virologic relapse. Patients with stage 2 or greater fibrosis on pretreatment biopsy were invited to undergo a long‐term follow‐up biopsy after their fourth year of follow‐up. One hundred twenty‐eight patients (85%) were followed through their fourth year, and long‐term follow‐up biopsies were obtained from 60 patients (40%). Forty‐nine patients had paired pretreatment and long‐term follow‐up biopsies blindly rescored. Forty of these patients (82%) had a decrease in fibrosis score, and 45 (92%) had a decrease in combined inflammation score. Ten patients (20%) had normal or nearly normal livers on long‐term follow‐up biopsy. Two patients with pretreatment cirrhosis developed hepatocellular carcinoma (HCC), and one died. All the other patients with pretreatment cirrhosis or advanced fibrosis had improved fibrosis scores on long‐term follow‐up biopsy. No patient had conclusive evidence of virologic relapse. Three patients had persistently elevated alanine aminotransferase levels; two of these had new liver disease. Conclusion: In a cohort of 150 patients with SVR followed for 5 years, the majority of patients had good outcomes. Serum virologic relapse was not seen, but two patients with pretreatment cirrhosis developed HCC, and one died. In a blind rescoring of 49 paired pretreatment and long‐term follow‐up biopsies, 82% improved fibrosis scores and 92% improved at least one component of inflammation. A minority of patients had normal or nearly normal liver tissue on long‐term follow‐up biopsy. Patients with cirrhosis pretreatment are at a low but real risk of HCC after SVR. (HEPATOLOGY 2009.)