High-dose interleukin-(IL-2) has been broadly studied in tumour therapy, yet it may be inhibitory to T-cell-dependent immunity. Therefore immune and tumour responses mediated by low-dose IL-2 were studied systematically with respect to the feedback organisation of immune responses. IL-2 was administered once daily at three dose levels: 0.18, 0.9, 4.5 MIU/m2 according to three different schedules requiring subcutaneous (s.c.) injection once weekly (four doses, stratum I), thrice weekly every other day (nine doses, stratum II), or five times weekly every other week (ten doses, stratum III). A total of 46 patients with advanced cancer were randomly assigned to one of the nine treatment groups. Systemic effects were induced at doses as low as 0.18 MIU/m2 IL-2 s.c. as demonstrated from measurable IL-2 serum levels, induction of circulating IL-6, a transient lymphopenia, and stimulation of delayed-type hypersensitivity (DTH) responses of the skin. Analysis of the different IL-2 schedules demonstrated (a) prolonged effects of once-weekly injections on DTH responses, lymphocyte and eosinophil counts, and (b) maximum increase of eosinophil counts and preferential expansion of activated NK cells with repeated injections every 48 h or 72 h (stratum II), while sequential treatment according to stratum III was found to be more potent in increasing the number of activated T cells. A tumour response was observed in 1/15 patients with renal cell carcinoma who experienced more than 50% tumour regression for 8 months; 12 patients had stable disease for 4 months (median). These data demonstrate prolonged immunological effects of ultra-low doses of s. c. IL-2 despite its short half-life. Furthermore, scheduling of IL-2 was found to affect immune responsiveness specifically as demonstrated by the differential effects on natural killer and T cell populations.