ObjectiveTo investigate the correlation between different RAS/BRAF mutation sites and the clinicopathological characteristics, metastatic sites, and prognosis of patients with colorectal cancer. MethodsA retrospective analysis was conducted on the clinicopathological data of 415 patients with stage Ⅰ –Ⅲ microsatellite stability (MSS) colorectal cancer who underwent radical surgery at the Department of Colorectal Surgery, The First Affiliated Hospital of Zhejiang University, and the Department of General Surgery, Gansu Provincial People’s Hospital, from March 1, 2017, to October 1, 2022, and had next-generation sequencing data. According to the presence and sites of RAS/BRAF mutations, patients were divided into five groups: RAS/BRAF wild-type group, KRAS G12 codon mutation group, KRAS G13 codon mutation group, BRAFV600E mutation group, and other RAS codon mutation group. The clinicopathological characteristics and prognostic differences between the four groups of RAS/BRAF mutant colorectal cancer patients and the RAS/BRAF wild-type colorectal cancer patients were compared. ResultsAmong stage Ⅰ –Ⅲ MSS colorectal cancer patients, there were 166 cases (40.0%) of wild-type RAS/BRAF without mutation, 124 cases (29.9%) of KRAS G12 mutation, 55 cases (13.3%) of KRAS G13 mutation, 23 cases (5.5%) of BRAFV600E mutation, and 47 cases (11.3%) of other RAS codon mutations. Clinicopathological characteristics analysis revealed that BRAFV600E mutation was associated with mucinous adenocarcinoma (P=0.033). Compared with the wild-type group, KRAS G12 mutation could increase the probability of metachronous lung metastasis (P=0.003) and reduce the probability of metachronous liver metastasis (P=0.013); the KRAS G13 mutation and other RAS mutations could increase the probability of metachronous lung metastasis (P=0.004, P=0.006). Univariate and multivariate Cox proportional hazards regression analysis showed that among the RAS/BRAF codon mutations, only KRAS G13 mutation was an independent prognostic factor for poor prognosis in stage Ⅰ –Ⅲ colorectal cancer. ConclusionsDifferent RAS/BRAF gene codon mutations are associated with distinct clinicopathological characteristics and organ metastatic sites in colorectal cancer. KRAS G13 codon mutation is an independent prognostic factor for poor prognosis in stage Ⅰ –Ⅲ colorectal cancer. It is recommended that routine detection of RAS/BRAF gene site mutations should be performed in stage Ⅰ –Ⅲ colorectal cancer patients to guide the follow-up management and help clinicians make rational clinical decisions after tumor recurrence.