Background: The BRAF and KRAS mutations have been proposed as prognostic markers in colorectal cancer (CRC). Of them, only the BRAF V600E mutation has been validated as prognostic for overall survival and survival after relapse, while the value of KRAS mutation is still unclear. Methods: In a cohort of 1423 stage II-III patients from the PETACC-3 clinical trial, the prognostic value of the BRAF and KRAS mutations was retrospectively assessed in all possible stratifications defined by the 5 factors (T and N stage, tumor site and grade, and microsatellite instability status), by log rank test for overall survival (OS), relapse-free survival (RFS), and survival after relapse (SAR). The presence of interactions was tested by Wald test. The significance level was set to 0.01 for Bonferroni-adjusted p-values (P*), and a second level for a trend towards statistical significance was set at 0.05 for unadjusted p-values (P). Results: BRAF mutation was a marker of poor OS only in microsatellite stable (MSS) and left-sided tumors, with no prognostic value in microsatellite instable (MSI-H) or right-sided tumors. In MSS/left-sided tumors, BRAF mutation represents a marker of higher risk than previously reported: OS HR=6.4 [95% CI: 3.6-11.5], P* < 0.0001. For SAR, BRAF was prognostic in more stratifications, with higher risk in MSS/left-sided tumors (HR=3.9 [95% CI: 2.1-7.2], P* = 0.0002) than in MSS/right-sided (HR=2.3 [95% CI: 1.2-4.4], P=0.01). A novel observation was that BRAF mutation was prognostic also for RFS, but only in MSS/left-sided tumors (HR=3.6 [95% CI:2-6.3], P*=0.0005]). Additionally, heterogeneity in OS and RFS among BRAF mutants was observed. In general, KRAS mutation did not reach the significance level required, but showed a trend to become a prognostic marker for RFS in MSS tumors with early lymph node involvement (N1) (HR=1.6 [95% CI:1.1-2.2], P=0.01). Conclusions: The prognostic utility of the BRAF and KRAS mutations has to be interpreted in the context of other factors. For the BRAF mutation, a clear interaction with MSI status and tumor site was observed, with BRAF mutation indicating a much higher risk in MSS/left-sided tumors than previously considered.