Background: The optimal regimen and chemotherapy intensity are still under investigation for neoadjuvant treatment of locally advanced rectal cancer (LARC). The CinClare trial has demonstrated improved pathologic complete response (pCR) with the addition of irinotecan to neoadjuvant chemoradiotherapy (CRT) guided by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotype in LARC. Here, we report the 5-year follow-up outcomes of the CinClare study. Methods: From November 2015 to December 2017, this randomized, open-label, multicenter, phase III trial enrolled 360 patients with LARC and assigned them in a 1:1 ratio to CapIriRT (radiation with capecitabine combined with irinotecan followed by irinotecan and capecitabine) or CapRT (radiation with concurrent capecitabine followed by oxaliplatin and capecitabine). Irinotecan dosing was guided by UGT1A1 genotype (80 mg/m(2) for *1/*1 and 65 mg/m(2) for *1/*28). The endpoints, including local control (LC), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS), were analyzed using the log-rank test, Cox proportional hazards regression and restricted mean survival time (RMST) test at the data cut-off date of June 2023. Results: With a median follow-up of 60 months, the CapIriRT group showed numerically higher 5-year LC (95.6% vs. 93.9%), 5-year DMFS (83.9% vs. 77.9%), 5-year DFS (77.7% vs. 70.6%), and 5-year OS rates (82.9% vs. 76.1%) than the CapRT group. Further RMST test also showed a statistically significant difference in DFS (P < 0.05) and a borderline difference in OS (P = 0.050). Among the UGT1A1 *1/*1 population, the CapIriRT group had significantly improved 5-year rates of DMFS, DFS, and OS (all P < 0.05). Patients achieving pCR also had significantly longer DFS and OS compared to non-pCR patients (P < 0.05). Conclusions: The addition of irinotecan guided by UGT1A1 genotype to a standard capecitabine-based scheme brings clinical benefits with improved LC, DMFS, DFS, and OS. Patients with the UGT1A1 *1/*1 genotype derived notable benefit from irinotecan, with improved survival outcomes. Achievement of pCR is crucial as it is associated with improved long-term survival. These findings support the integration of genomic testing into clinical practice to achieve a personalized irinotecan dosing regimen, which can optimize efficacy and safety.