Introduction: Sunitinib is a standard of care first line treatment for patients with metastatic renal cell carcinoma (RCC). Sunitinib standard dose is 50 mg once daily for 4 consecutive weeks followed by 2 weeks’ off (4/2 schedule). Long-term and high exposure to this medication lead to severe adverse events (AEs); therefore, this trial was done to find the best schedule which gives the best outcome with minimal toxicity. Materials and methods: Seventy patients were randomly assigned into 2 groups, then received 50 mg/day of sunitinib. Group 1 (40 patients) received sunitinib for 4 consecutive weeks followed by 2 weeks off (4/2 schedule) while 30 patients were admitted to group 2 with 2 weeks on and 1 week off (2/1 schedule). Results: All patients (100%) had significantly higher AEs on schedule 4/2 vs. 73.3% on schedule 2/1 (p = 0.001). Furthermore, the grade 3 AEs on schedule 2/1 were significantly lower than those on schedule 4/2 (26.7% vs. 82.5%) respectively (p = 0.001), such as fatigue, diarrhea, hypertension, hand foot syndrome (HFS) and mucositis. Progression-free survival (PFS) rate was significantly higher in 2/1 schedule (60.9% vs. 38.6%) than in 4/2 schedule (p < 0.008). Multivariate analysis suggested that: age > 60 years, poor International Metastatic RCC Database Consortium (IMDC) risk category, tumor size > 10 cm and treatment schedule (group 1) were poor prognostic factors of PFS. Conclusions: Our study supported the use of 2/1 schedule of sunitinib in patients with metastatic RCC because of lower toxicity profile and better efficacy with improved PFS in comparison to 4/2 schedule. lower toxicity profile and better efficacy with improved PFS in comparison to 4/2 schedule.