Background: Sunitinib is an antiangiogenic agent indicated for the treatment of metastatic renal cell carcinoma (mRCC). Sunitinib is given in a 4 week on, 2 week off (4/2) schedule. Significant toxicities are observed in patients in the 3^rd and 4^th weeks of therapy. We hypothesized that a 2 week on, 1 week off (2/1) schedule would provide improved toxicity without compromising efficacy. Methods: A multicenter, single arm study was performed, with patients initiating sunitinib 50mg on a 2/1 schedule. Schedule and dose alterations were performed if grade > 3 toxicities were observed. The primary objective was to determine the percentage of patients who experienced grade > 3 fatigue, diarrhea, or HFS. The sample size of 60 patients was selected to ensure the upper bound of a 95% confidence would fall below standard schedule rate of 25%-30% if sample rate was 10%-15%, respectively. Secondary outcomes included response rate (RR), progression free survival (PFS) and dose reductions. Results: Between August 2014 and April 2016, 60 patients were enrolled, and 59 treated. Patients had a median age of 65.5 years (ranging from 45-92). 24% of patients (14/59) had grade 3 or higher fatigue, diarrhea, or HFS (95% CI: 13.6%, 36.6%). This is similar to the average of the 4 week on, 2 week off schedule of 25%-30%, and the lower bound of the confidence interval is in the center of our target rate of 10%-15%. Among events at least possibly related to study drug, patients were most likely to experience the expected events of diarrhea (75% with 5 grade 3 events), fatigue (71% with 6 grade 3 events), and HFS (54% with 3 grade 3 events). 22 (37%) patients responded (25.0%, 50.9%). Among patients with secondary endpoint data available, median PFS was 19.3 months (95% CI: 8.2, NR) and 33/56 (59%) of patients underwent dose reduction. Conclusions: Sunitinib administered in a 2/1 schedule in this study did not result in a lower rate of grade 3 or higher fatigue, diarrhea or HFS when compared to historical data from trials employing a 4/2 schedule. However, efficacy data showed robust response rate and a prolonged PFS, suggestive of long-term tolerability in patients receiving sunitinib on a 2/1 schedule. Evaluation of toxicity kinetics and patient quality of life is ongoing. Clinical trial information: NCT02060370