Interferon alpha and ribavirin (RBV) combination therapy is associated with decreases in haemoglobin (Hb) concentrations and anaemia. The aim of this analysis was to better characterize the magnitude and frequency of Hb changes and risk factors. This retrospective analysis evaluated treatment-related changes in Hb in 677 patients who participated in either of two interferon alpha-2b plus RBV studies for chronic hepatitis C virus (HCV) infection. Study 1 included 192 interferon alpha-naïve patients randomized to receive RBV 1000–1200 mg/day plus interferon alpha-2b 3 million IU daily or three times weekly for 48 weeks. Study 2 included 485 interferon alpha-experienced patients randomized to receive RBV 1000-1200 mg daily plus interferon alpha-2b 3 million IU daily or three times weekly for 4 weeks, followed by three times weekly dosing for 44 weeks. More than 50% of all patients experienced a decrease in Hb ≥30 g/L. Women were 4.4 times as likely as men to experience a Hb level of <100 g/L; however, men were at a 40% higher risk to experience a Hb decline of >30 g/L from baseline. Daily use of interferon alpha-2b did not impact the magnitude of Hb decrease. In this pooled analysis, RBV dose reduction resulted in increases in Hb concentration of approximately 10 g/L. Lower baseline creatinine clearance, higher baseline Hb levels and increased age were independently associated with increased risk of Hb decreases of >27.7%. Lower baseline weight was not associated with increased risk of Hb decrease. Substantial Hb decreases occur frequently with interferon alpha/RBV combination therapy. Sex, the magnitude of the Hb decline and renal function are potentially important factors to consider in patients receiving RBV. Further research is needed to determine the impact on virological response and to develop strategies to manage the medical consequences.