Anemia is a common complication of hepatitis C (HCV), and antiviral treatment can further increase this risk. We present the case of a 59-year-old man with HCV treated with ribavirin and pegylated interferon alpha (INF-α) who presented with severe anemia. Two months after initiating treatment his hemoglobin dropped from 14.2 to 5.0 g/dL. There was no evidence of bleeding or hemolysis, and a bone marrow biopsy revealed pure red cell aplasia (PRCA). Evaluations for acute cytomegalovirus and parvovirus B19 were negative. There was no evidence of malignancy or thymoma. The INF-α and ribavirin treatment were determined to have caused the PRCA, and withdrawal of the medications led to PRCA remission. INF-α and ribavirin have become the standard treatment for HCV. While these medications offer a potential cure, they are often poorly tolerated due to frequent side effects including anemia. Patients who are receiving treatment with ribavirin and INF-α warrant close monitoring for development of anemia, and PRCA should be considered in all patients in whom reticulocytopenic anemia develops.