Background: Treatment of metastatic renal cell carcinoma (mRCC) with sunitinib can be associated with toxicity leading to dose reduction. Maintaining adequate sunitinib dosing and avoiding dose interruptions that lower drug levels are essential for optimizing clinical efficacy. Standard sunitinib schedule is 4 weeks of treatment and 2 weeks of rest (schedule 4/2). Empirically in clinical practice, several metastatic RCC patients at The Cleveland Clinic (CCF) have been changed from a 4/2 schedule to a 2 weeks on /1 week off (2/1) schedule after experiencing toxicity in an attempt to maintain daily dose but reduce toxicity. Methods: The medical records of mRCC patients who were changed to a 2/1 schedule of sunitinib at CCF were retrospectively reviewed. Patient toxicity on each schedule was recorded during routine clinic visits and graded according to the Common Toxicity Criteria, version 4.0. Results: 21 patients were identified: 71% male, 78% clear cell histology, and 29% prior systemic therapy. All but one had prior nephrectomy. 95% of patients on the 4/2 schedule had grade 3 or 4 toxicity which led to the schedule change to 2/1. No grade 4 toxicities were observed on the 2/1 schedule, and 33% of patients experienced grade 3 toxicity (p = 0.0001 for comparison of worst grade toxicity on 4/2 versus 2/1). Two of the most common toxicities, fatigue and hand-foot syndrome (HFS), were significantly less frequent on the 2/1 schedule than on the 4/2 schedule (fatigue 52% all grade/33% grade 3 on 4/2 versus 33%/14% on 2/1; HFS 33%/29% on 4/2 versus 14%/0% on 2/1; p =.04 for both). Median overall treatment duration on the 4/2 schedule was 13.5 months (range 1.1-60.6 months) and median overall treatment duration on the 2/1 schedule was 24.4 months (range 1.3 to 67.6+ months). Conclusions: Treatment with sunitinib on a 2/1 schedule is associated with significantly decreased toxicity in patients who initially experience grade 3 or greater toxicity on the 4/2 schedule and can extend treatment duration considerably. Prospective clinical trials are required to define the optimal schedule of sunitinib to balance efficacy and toxicity.