Background: UGT1A1*28 polymorphism is associated with neutropenia and diarrhea in previous reports, while this study tried to investigate correlation with other toxicities like vomiting. Patients and Methods: This is a prospective case control study including all eligible cases of advanced colorectal cancer. The genotypes of UGT1A1*28 was assessed in the peripheral blood and/or in tissues by PCR. Patients were divided into two groups, Group 1: patients with no mutation, Group 2: patients with homo or hetero mutation. All patients received standard IFL regimen. Primary objectives were: 1) comparison between the 2 groups as regard vomiting, 2) assessment of the incidence of UGT1A1*28 polymorphism. Secondary objectives were: comparison between the 2 groups as regard: neutropenia, diarrhea, treatment delay, progressive diseases (PD), progression free survival (PFS) and overall survival (OS). Results: 46 cases of advanced colorectal cancer present to National Cancer Institute, Cairo University, aged between 19 and 71 years with a median age of 45 years were included and followed up during the period from September 2010 to January 2013 with a median follow-up of 9 months. UGT1A1*28 polymorphism was present in 20 patients (43%), of whom 15% are homozygous. Grade (II-IV) vomiting was found in 8.3% of Group 1 versus 52.5% of Group 2 (P = 0.01). Grade (II-IV) neutropenia was found in 20.8% of Group 1 versus 64.7% of Group 2 (P = 0.03). Grade (II-IV) diarrhea was found in 37.5% of patients of Group 1 and 27.5% of patients with Group 2. (P = 0.75). Treatment delay occurred in 29.16% of Group 1 versus 72.4% of Group 2 (P = 0.02). 25% of Group 1 showed PD versus 25% of Group 2 (P = 0.8). 1-year PFS was 19% in Group 1 versus 23% in Group 2 (P = 0.8) while there was a trend towards better OS in Group 1 (47% versus 35%) (P = 0.07). Conclusions: UGT1A1*28 polymorphism is present frequently (43%) in a Caucasian population and is associated with more vomiting, neutropenia and treatment delay.