OBJECTIVE To evaluate the toxicity and activity of thalidomide in patients with advanced metastatic renal cell cancer and to measure changes of one angiogenic factor, vascular endothelial growth factor (VEGF)165, with therapy. METHODS 29 patients were enrolled on a study of thalidomide using an intra-patient dose escalation schedule. Patients began thalidomide at 400 mg/d and escalated as tolerated to 1200 mg/d by day 54. Fifty-nine per cent of patients had had previous therapy with IL-2 and 52% were performance status 2 or 3. Systemic plasma VEGF165 levels were measured by dual monoclonal ELISA in 8 patients. RESULTS 24 patients were evaluable for response with one partial response of 11 months duration of a patient with hepatic and pulmonary metastases (4%), one minor response, and 2 patients stable for over 6 months. Somnolence and constipation were prominent toxicities and most patients could not tolerate the 1200 mg/day dose level. Systemic plasma VEGF165 levels did not change with therapy. CONCLUSIONS These results are consistent with a low level of activity of thalidomide in renal cell carcinoma. Administration of doses over 800 mg/day was difficult to achieve in this patient population, however lower doses were practical. The dose-response relationship, if any, of thalidomide for renal cell carcinoma is unclear.