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Interleukin-2 (IL-2) and interferon-β (IFN-β ) have demonstrated activity against lymphoid malignancies, presumably mediated by the augmentation of lymphokine-activated killer (LAK) cell and natural killer (NK) cell activity. There is in vitro and in vivo evidence to suggest that the combination of IL-2 and IFN-β is synergistic. The Cancer and Leukemia Group B (CALGB) conducted a randomized phase II trial of IL-2 with or without IFN-β in 49 patients with relapsed or refractory non-Hodgkin's lymphoma (NHL). Overall toxicity was severe, with 17 patients experiencing life-threatening toxicity. Three patients had treatment-related deaths. Responses were noted in seven patients (17%). There were no meaningful differences between treatment arms in toxicity profile, response rate, or modulation of in vivo NK and LAK activity. We conclude that IL-2 with or without IFN-β is not effective therapy for NHL in the doses and schedule used in this study.