OBJECTIVE: A Phase I study of subcutaneous recombinant interleukin-2 (rIL-2). DESIGN: Sixteen patients with advanced HIV infection receiving 600-1200 mg zidovudine per day were divided into three groups, which received sequentially 0.2 x 10(6), 0.7 x 10(6) or 2 x 10(6) units/m2 per day of rIL-2 subcutaneously 5 consecutive days. SETTING: Five-day admission to an academic tertiary care hospital. PATIENTS, PARTICIPANTS: Sixteen unblinded, non-randomized volunteers. INTERVENTIONS: Subcutaneous rIL-2. MAIN OUTCOME MEASURES: Tolerance, toxicity, hematologic, immunologic and antiviral responses. RESULTS: rIL-2 was well-tolerated at the highest dosage, except in two patients who developed significant lymphopenia by the second day of rIL-2 administration, with rebound within 48 h after rIL-2 therapy. The number of eosinophils, CD4+ and CD8+ cells, and percentage of CD16+ (natural killer) cells, remained elevated above baseline for up to 10 weeks. Circulating rIL-2 receptor levels increased transiently during and immediately following rIL-2 administration. A twofold increase in natural killer cell activity against uninfected and HIV-infected targets was observed, but did not persist beyond 10 weeks following rIL-2 administration. There was a transient decrease in blastogenesis to phytohemagglutinin of patients receiving the highest dose of r-IL-2, but no significant change in viral burden. CONCLUSIONS: Subcutaneous rIL-2 in advanced HIV-infected patients on zidovudine was tolerated with side-effects similar to intravenous IL-2.