BACKGROUND The treatment of advanced renal cell cancer remains unsatisfactory, therefore new combination regimens such as thalidomide and IL-2 are of interest. A phase I trial of SC IL-2 and oral thalidomide was performed to identify the toxicity, maximum tolerated dose (MTD) and preliminary clinical activity of this regimen. METHODS 33 patients with advanced/metastatic RCC were enrolled. An established 8-week outpatient schedule of subcutaneously administered IL-2 in escalating doses, days 1-5, for 6 weeks with a 2 week rest was utilized with daily oral thalidomide. Cohorts of 4-6 patients were treated at 4 dose levels. RESULTS Toxicity was moderate to severe and related to dose level. All patients developed fever, chills and fatigue. 29/33 patients developed < or = Grade 2 desquamation of hands and feet and/or rash. Dose limiting toxicity (DLT) included Grade 3 neutropenia and pulmonary embolus. The maximum tolerated dose (MTD) of IL-2 and thalidomide was 9.0 MIU/m2 s.c. days 1-5, weeks 1 to 6 and 100 mg p.o. daily, respectively. A median of 2 cycles of therapy was administered (range 1-9). 2/33 patients responded (1 CR--prior IL-2 therapy, 1 PR--no prior therapy) with an overall response of 6% (95% CI, 1-20%). One minimal response was converted to a surgical CR (remains disease free at 24 + months). CONCLUSIONS Outpatient administration of IL-2 and thalidomide is possible with acceptable toxicity. Further evaluation of this regimen is underway.