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BACKGROUND: Risk of irinotecan-related severe toxicity is significantly higher in patients carrying 2 dysfunctional UGT1A1 gene variants, characterized as poor metabolizers (PMs), following standard irinotecan dosing. Since 2020, we implemented UGT1A1 genotype-guided dosing of irinotecan in routine clinical practice to reduce toxicity in PMs. This study evaluates its impact on severe toxicity in a real-world cohort. PATIENTS AND METHODS: Our study cohort included adult patients who received UGT1A1 genotype-guided irinotecan dosing at 6 Dutch hospitals between December 2020 and April 2024. Patients were included in the primary analysis if irinotecan was dosed according to UGT1A1 genotype (ie, 100% ±10% dose intensity for intermediate and normal metabolizers [IM/NMs] and 70% ±10% for PMs) in at least cycle 1. Toxicities, hospitalizations, and treatment alterations were collected for cycles 1-3 and graded according to CTCAE version 5.0. Endpoints were compared between PMs with a 70% starting dose and fully dosed IM/NMs. RESULTS: A total of 501 patients were included in the primary analysis; 54 of whom were PMs (10.8%). Baseline characteristics were evenly distributed between groups. The incidences of overall severe toxicity (29.6% vs 34.0%; P=.52), febrile neutropenia (3.7% vs 5.8%; P=.76), severe neutropenia (17.0% vs 17.8%; P=.88), severe diarrhea (13.0% vs 15.0%; P=.69), and toxicity-related hospitalization (14.8% vs 21.7%; P=.24) were comparable between dose-reduced PMs and fully dosed IM/NMs. In a secondary analysis, 9 UGT1A1 PMs who received an unintended full irinotecan dose experienced more severe toxicity than PMs with a 70% starting dose (overall severe toxicity: 77.8% vs 29.6%; P=.009). CONCLUSIONS: UGT1A1 genotype-guided dosing of irinotecan improves patient safety and treatment tolerability of irinotecan. A 70% starting dose of irinotecan for UGT1A1 PMs is necessary to normalize the risk of severe toxicity to that of IM/NMs.