Associations between colorectal cancer (CRC) survival and mutations in mediator of MAPK/ERK (RAS-BRAF-MEK-ERK) and PIK3CA/AKT signaling pathways have been reported. The objective of this study was to evaluate the influence of mutations in the EGFR pathway (KRAS, NRAS, BRAF and PIK3CA) on overall survival in CRC. We conducted a retrospective observational cohort study comprising 194 paraffin tumor samples from patients diagnosed with colorectal cancer were analyzed for KRAS codons 12, 13 and 61, NRAS codons 12, 13 and 61, BRAF and PIK3CA exons 9 and 20 gene mutations. Multivariate analysis confirmed that patients with ECOG of 0 presented lower risk of death (HR = 0.17, CI95%, 0.10 -0.31, p = 1656.10-9) compared to a higher ECOG (Table 4). The only independent genetic association was between PIK3CA20 mutation (H1047Y; rs121913281) and higher risk of death (HR = 8.93, CI95%, 1.20-66.57, p = 0.03268). No association was found between the rest of the mutations analyzed and overall survival. To explore the effect of mutations in patients with different degrees of ECOG, a stratified analysis was performed. Multivariate analysis in patients with ECOG 0 group confirmed the association between mutations of PIK3CA and an increased risk of death: E545K (HR = 5.49, CI95%, 1.28-23.51, p = 0.021720) and H1047Y (HR = 53.49; %, 4.63-617.40, p = 0.001429). In conclusion, our results show PIK3CA gene mutations may predict the overall survival of CRC patients, positioning PIK3CA as a potential biomarker for survival in CRC.