SummaryThe antitumor mechanisms of the interferons (IFN) have yet to be fully elucidated. Augmentation of natural killer (NK) cell activityin vitroandin vivoby IFN has regularly been assessed in clinical trials. We have measured NK activity against K562 target cells at various effector-to-target ratios, in patients receiving leukocyte IFN-α (HuLeIFN) in various schedules, as well as T-cell subsets determined by indirect immunofluorescence using Leu series monoclonal antibodies (Becton-Dickinson). The effect of HuLeIFN on the endocrine system has also been examined in selected trials. The preliminary results of these studies reveal that NK activity rose during the first 8 days of HuLeIFN therapy in patients with initially low levels of target cell lysis (<50% NK activity at either 50:1 or 25:1 ratios). Tachyphylaxis, with a decremental effect of HuLeIFN on NK activity, ensued during treatment, whether at the same or escalated doses. NK activity rose repeatedly during intermittent schedules of i.m. HuLeIFN given daily X 5 every 21 days with escalation cycles. A decreasing trend in the ratio of Leu 3a to Leu 2a (helper phenotype/ suppressor phenotype) was also seen overall. Of the endocrine parameters evaluated, the only remarkable finding was an increase in serum cortisol level following ACTH stimulation following HuLeIFN. Intramuscular HuLeIFN has been shown to augment NK activity, to perturb the T-cell-lymphocyte balance, and to affect the pituitary-adrenal axis invivo.