High relapse rates during the first year after autologous stem cell transplantation (ASCT) for multiple myeloma or non-Hodgkin lymphoma are due to the failure of high-dose chemotherapy to eradicate minimal residual disease. Post-ASCT immunorecovery studies have shown that quantities of natural killer (NK) cells return to normal within 1 month post-ASCT in contrast to the recovery of T and B cell populations (up to 1 year). Preclinical studies have demonstrated that NK cells have potent antitumor activity. IL-2 and IFN-α enhance NK-cell activity. We investigated the efficacy of IL-2 and IFN-α to up-regulate NK-cell cytotoxicity at 14 days post ASCT. Twenty patients undergoing ASCT had PBMCs collected pretransplantation and at 14 days post transplantation. PBMCs (effector cells) from each blood sample were incubated in vitrowith IFN-α and IL-2 at 10000 IU/ml. NK cell activity was determined by sodium chromate 51 Cr release assay for lysis of K562 target cells. IL-2 and IFN-α each increased lysis of K562 cells compared with placebo (effector-to-target ratio, 50: 1, P< 0.001). Increased NK cell activity occurred in samples from all patients. IL-2 and IFN-α up-regulated NK cell activity at 14 days post ASCT. They may be useful as immunomodulators as early as 14 days post ASCT to eradicate or control minimal residual disease. Bone Marrow Transplantation (2001) 28, 673–680.