The objective was to evaluate DNA mutations of KRAS, BRAF, and PIK3CA and their clinicopathological correlations with colorectal cancer (CRC) and to identify their contribution to distant metastases in CRC. A total of 148 tumor samples were obtained from patients with CRC in the Shandong Tumor Hospital and Institute between January 2008 and December 2009. DNA was extracted for polymerase chain reaction amplification and pyrosequencing to evaluate mutations of KRAS, BRAF, and PIK3CA, and clinicopathological correlations of these mutations with CRC [including age, gender, tumor location, pathological type, tumor-node-metastasis (TNM) classification, and distant metastatic status] were analyzed. KRAS, BRAF, and PIK3CA mutation rates were identified in 46 (31.1 %), 11 (7.4 %), and 14 (9.5 %) of the total 148 CRC tumor samples, respectively. Neither mutation had significant correlation with age, gender, size and location of the tumor, and pathological type. KRAS, BRAF, and PIK3CA mutations were found in 14 (66.7 %), 3 (14.3 %), and 8 (38.1 %) of the 21 distant metastatic colorectal tumor samples, respectively. The relative risks of distant metastasis for KRAS, BRAF, and PIK3CA mutations were 30.4 versus 6.8 % (P = 0.001), 27.3 versus 13.1 % (P = 0.191), and 57.1 versus 9.7 % (P < 0.001) (5-year risks), respectively. Patients with either KRAS or PIK3CA mutations are more susceptible to distant metastasis. Thus, these two mutations might be used as independent predictors of distant metastatic CRC.