BACKGROUND: Administration of recombinant high dose interleukin-2 (IL-2) can mediate tumor regression in patients with metastatic melanoma and renal carcinoma. Significant trends in the safety of high dose IL-2 administration at a single institution over a 12-year study period were reviewed. METHODS: A consecutive series of 1241 metastatic cancer patients treated with intravenous bolus infusions of IL-2 (720,000 IU/kg every 8 hours) were evaluated for the incidence of specific treatment-related toxicities, the maximum number of administered IL-2 doses, and objective response rates. RESULTS: Significant decreases in the incidence of Grade 3 and/or Grade 4 toxicities were found when the initial group of 155 patients was compared with the final group: Grade 3/4 line sepsis (18% vs. 4%), Grade 3/4 diarrhea (92% vs. 12%), Grade 4 neuropsychiatric toxicity (19% vs. 8%), pulmonary intubations (12% vs. 3%), Grade 3/4 hypotension (81% vs. 31%), and Grade 4 cardiac ischemia (3% vs. 0%). No treatment-related deaths were noted in the final 809 patients. Laboratory abnormalities, such as increased creatinine, hyperbilirubinemia, and thrombocytopenia, were less severe, whereas percent weight gain remained stable over the 12-year period. The maximum number of administered IL-2 doses during the first cycle of therapy decreased from an initial median of 13 doses to 7 doses per first treatment cycle. No significant differences in overall and ongoing complete response rates to high dose bolus IL-2 were observed for melanoma patients (two-tailed P value = 0.40 and 1.0, respectively), or renal carcinoma patients (two-tailed P value = 0.92 and 0.89, respectively) over the study period. CONCLUSIONS: Progressive reduction in morbidity and mortality was found with the systemic administration of high dose IL-2-based therapies over the 12-year study period. The improvement in safety most likely reflects the development of strategies to screen eligible patients, optimize therapeutic conditions, and judiciously terminate dosing when significant toxicities are noted. Despite these interventions, the overall and ongoing complete response rates for melanoma and renal carcinoma have not shown significant compromise. These trends suggest that high dose IL-2 can be safely administered to metastatic cancer patients under the current treatment guidelines and result in durable responses in a small subset of patients.