Biologic and clinical observations suggest that combining imatinib with IFN-a may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission either to receive a combination of pegylated IFN-a2b (Peg-IFN-a2b) 50 µg weekly and imatinib 400 mg daily (n = 56) or to receive imatinib 400 mg daily monotherapy (n = 56). The primary endpoint was the major molecular response (MMR) rate at 12 months after randomization. In both arms, 4 patients (7%) discontinued imatinib treatment (1 because of blastic transformation in imatinib arm). In addition, in the combination arm, 34 patients (61%) discontinued Peg-IFN-a2b, most because of toxicity. The MMR rate at 12 months was significantly higher in the imatinib plus Peg-IFN-a2b arm (82%) compared with the imatinib monotherapy arm (54%; intention-to-treat, P = .002). The MMR rate increased with the duration of Peg-IFN-a2b treatment (<12-week MMR rate 67%, > 12-week MMR rate 91%). Thus, the addition of even relatively short periods of Peg-IFN-a2b to imatinib markedly increased the MMR rate at 12 months of therapy. Lower doses of Peg-IFN-a2b may enhance tolerability while retaining efficacy and could be considered in future protocols with curative intent.