4036 Background: Several studies with limited patient (pt) numbers reported a higher risk of severe toxicity in homozygous UGT1A1*28 (*28/*28) pts treated with IRI, with inconsistent findings due to IRI dosage heterogeneity. To better evaluate the risk attributable to IRI in *28/*28 pts, we took advantage of PETACC 3, a large adjuvant trial with 3005 COC pts, where 91% of the pts treated in arm A received IRI at 180mg/m2 q2w with infusional 5-FU/FA (FOLFIRI). Methods: DNA was extracted from normal formalin fixed paraffin embedded tissue. UGT1A1 genotype (Ge) was assessed by PCR and fragment sizing. Frequency of grade (Gd) 4 neutropenia (N) and of febrile neutropenia (FN) according to UGT1A1 Ge status (Normal: *1/*1, heterozygous: *1/*28 or homozygous: *28/*28) was assessed by chi-square tests and Cochran-Armitage trend tests. Logistic regression (LR) was used to test the impact of other variables (Var) on toxicity outcomes. Results: Of the 1,405 patients genotyped 44% are 1*/1*, 43% *1/*28 and 13% *28/*28. Decreased occurrence (occ) of Gd ≥3 diarrhea with Ge *28/*28 in both arms was reported elsewhere (ASCO GI 2008, abstr #277). Gd 4 N occ in arm A (A) is 9% and 3.2% in arm B (B). Gd 4 N occ according to Ge (*1/*1 and *1/*28 vs *28/*28) is 7.9% vs 16.1% (p=0.013, odds ratio (OR) 2.3 [95%CI 1.2–4.3]) in A, and 3.5% vs 1.4% (p=0.54) in B. FN occ in A is 5.2% and 1.76% in B. FN occ according to Ge (*1/*1, *1/*28 and *28/*28) is 6.5%, 2.2% and 11.5% (p=0.002 for *1/*1 vs *1/*28 vs *28/*28 and p=0.009, OR 3.0 [1.4–6.4] for *28/*28 vs all others) in A, and 1.7%, 1.6% and 2.7% (p=0.80) in B. Multiple LR analysis in A looking at age <60, sex, PS (1–0), bilirubin (0.5 x ULN) and Ge *28/*28 shows Female sex (FS) (OR 2.6 [1.4–4.6]) Ge *28/*28 (OR 2.5 [1.3–4.9]) PS (OR 2.0 [1.1–3.7]) and age (OR 0.6 [0.3–0.9]) to be significant as Var influencing Gd 4 N. If only cycle 1 is considered, the only significant Var influencing Gd 4 N are FS (OR 4.1 [1.8–9.6], p=0.0011) and UGT1A1 (OR 2.6 [1.05–6.5], p<0.04). Conclusion: The risk of developing grade 4 N and FN with FOLFIRI is increased in *28/*28 pts. However, FS is a stronger predictor of Gd 4 N than UGT1A1 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Oncology Pfizer Oncology Pfizer Oncology