Objective: To investigate the clinicopathological characteristics of PIK3CA gene mutation in stage III colorectal cancer and its impact on the response to adjuvant chemotherapy with the XELOX (oxaliplatin + capecitabine) regimen. Methods: A retrospective analysis was performed on the clinical data of 120 patients with stage III colorectal cancer who received adjuvant chemotherapy with the XELOX regimen following radical resection at our hospital between January 2022 and January 2025. Based on the results of PIK3CA gene testing in postoperative tumor tissues, the patients were divided into a mutation group (22 cases) and a wild-type group (98 cases). The baseline clinicopathological characteristics, XELOX chemotherapy-related indicators, and differences in recurrence, metastasis, and mortality rates within one year after surgery were compared between the two groups. Univariate and multivariate Logistic regression analyses were used to identify independent influencing factors for recurrence, metastasis, or death within one year after surgery. Results: The PIK3CA mutation rate was 18.33% (22/120). There were no statistically significant differences between the two groups in terms of age, gender, degree of differentiation, T stage, or N stage (P > 0.05). The proportion of right-sided colon cancer in the mutation group (54.55%) was higher than that in the wild-type group (32.65%), although the difference did not reach statistical significance (P > 0.05). Regarding chemotherapy-related indicators, the number of chemotherapy cycles and relative dose intensity in the mutation group were significantly lower than those in the wild-type group (P < 0.05). There were no statistically significant differences between the two groups in the proportion of planned cycles completed, the proportion of dose reductions/delays, or the incidence of adverse reactions (P > 0.05). The rate of recurrence, metastasis, or death within one year after surgery was 22.73% (5/22) in the mutation group and 12.24% (12/98) in the wild-type group, with no statistically significant difference (P > 0.05). Univariate and multivariate Logistic regression analyses showed that PIK3CA mutation, N2 stage, and right-sided colon location were not independently associated with recurrence, metastasis, or death within one year (P > 0.05). Conclusion: The incidence of PIK3CA mutation in stage III colorectal cancer is 18.33%, showing a certain correlation with right-sided colon cancer. Patients with PIK3CA mutations receiving XELOX adjuvant chemotherapy showed significantly reduced numbers of chemotherapy cycles and relative dose intensity, but no independent statistical association with the risk of recurrence within one year was observed. Future studies with expanded sample sizes and extended follow-up periods are needed for further verification.