The aim of the study was to evaluate the toxicity and efficacy of oral extended continuous temozolomide in patients with progressive metastatic renal cell carcinoma (RCC) not responding to immunotherapy after removal of the primary tumor. Patients with progressive metastatic RCC received protracted temozolomide 100 mg/m2 orally on days 1-21 every 28 days. Response was assessed after 2 cycles to be followed by another 2 cycles in the absence of progression. After 4 cycles only patients with further remission and acceptable toxicity were to continue. No objective responses were observed in 12 patients and the trial was stopped prematurely in stage 1. Six patients remained stable during 4 cycles of temozolomide (4 months), only one of these remained stable for another 2 months after having stopped treatment. Five patients progressed after the initial 2 cycles and one after the first cycle. Overall survival was 15.5 months (range 1-36 months). Repeated cycles of 3 weeks oral temozolomide 100 mg/m2 followed by one week rest proved tolerable though this regimen may only have limited activity against metastatic RCC.