This retrospective, observational study compared the clinical outcomes and adverse events (AEs) in RAS wild-type metastatic colorectal cancer (mCRC) patients treated with cetuximab or bevacizumab plus FOLFIRI with UGT1A1 genotyping and irinotecan dose escalation as the first-line therapy. In total, 173 patients with mCRC with RAS wild type were enrolled. Among them, 98 patients were treated with cetuximab, whereas 75 patients were treated with bevacizumab. All patients received irinotecan dose escalation based on UGT1A1 genotyping. Over a median follow-up of 23.0 months [interquartile range (IQR), 15.0-32.5 months), no significant differences were observed between the cetuximab and bevacizumab groups in PFS [18.0 months versus 14.0 months; 95% confidence interval (CI), 0.517- 1.027; hazard ratio (HR), 0.729; P = 0.071], OS (40.0 months versus 30.0 months; 95% CI, 0.410-1.008; HR, 0.643; P = 0.054), ORR (65.3% versus 62.7%; P = 0.720), DCR (92.8% versus 86.7%; P = 0.175)...Our results revealed that patients with wild-type RAS mCRC, regardless of biologics, with UGT1A1 genotyping can tolerate escalated doses of irinotecan and potentially achieve a more favorable clinical outcome without significantly increased toxicity.