Background: Sunitinib is a standard of care in first line mRCC; however, an increasing percentage of treatment-related adverse events are observed in the last 2 treatment weeks of the standard schedule 4/2 (4-weeks-on/2-weeks-off). In a multicenter, retrospective study, we evaluated the efficacy and safety of a modified 2/1 schedule (2-weeks-on/1-week-off), largely used in Italy based on a favorable initial experience. Methods: Data from all consecutive patients (pts) treated in 24 Italian centers with sunitinib on schedule 2/1 were analyzed according to the following groups: Group A, pts moved to schedule 2/1 because of treatment-related toxicities during initial therapy using schedule 4/2; Group B, pts treated ab initio with schedule 2/1, mainly because of poorer clinical conditions. A small group of pts treated with schedule 4/2 served as a control (Group C). Results: 276 consecutive pts treated from November 2005 to August 2013 were analyzed, including 249 treated with schedule 2/1 (Group A, n=208; Group B, n=41; respectively, median age 62 and 61 years; clear cell 94.7% and 87.8%; MSKCC good/intermediate/poor 47.1%/46.6%/6.3% and 36.5%/53.7%/9.8%; brain metastases 3.8% and 9.8%) and 27 pts in Group C (median age 59 years; clear cell 96.3%; MSKCC good/intermediate/poor 22.2%/70.4%/7.4%; no brain metastases). In Group A, the median treatment duration (TD) was 28.2 months (m) (with a median of 4.3 on the initial schedule 4/2 and 19.7 on the following schedule 2/1); median progression-free survival (PFS) was 38.6 m (95% CI, 24.0-58.6). In Group B (with less clear cell cases and more pts of intermediate risk or with brain metastases) median TD was 7.8 m and median PFS was 9.6 m (95% CI, 6.3-14.2). Median TD in Group C was 10.4 m. Maximum toxicity grade (≥3) and specific toxicities such as fatigue and hypertension were significantly reduced on schedule 2/1 in Group A compared with the initial schedule 4/2 (respectively, 8% vs 46% and 0% vs 10%, p < .001, and 2% vs 9%, p = .007). Conclusions: In our experience, sunitinib on a modified schedule 2/1 has an improved safety profile and increased efficacy compared with schedule 4/2. Prospective evaluation of this schedule is warranted.