AbstractBackgroundCurrent knowledge on prognostic biomarkers (especially BRAF^V600E/RAS mutations) in metastatic colorectal cancer (mCRC) is mainly based on mCRC patients with proficient mismatch repair (pMMR) tumors. It is uncertain whether these biomarkers have the same prognostic value in mCRC patients with deficient mismatch repair (dMMR) tumors.MethodsThis observational cohort study combined a population‐based Dutch cohort (2014–2019) and a large French multicenter cohort (2007–2017). All mCRC patients with a histologically proven dMMR tumor were included.ResultsIn our real‐world data cohort of 707 dMMR mCRC patients, 438 patients were treated with first‐line palliative systemic chemotherapy. Mean age of first‐line treated patients was 61.9 years, 49% were male, and 40% had Lynch syndrome. BRAF^V600E mutation was present in 47% of tumors and 30% harbored a RAS mutation. Multivariable regression analysis on OS showed significant hazard rates (HR) for known prognostic factors as age and performance status, however showed no significance for Lynch syndrome (HR: 1.07, 95% CI: 0.66–1.72), BRAF^V600E mutational status (HR: 1.02, 95% CI: 0.67–1.54), and RAS mutational status (HR: 1.01, 95% CI: 0.64–1.59), with similar results for PFS.ConclusionBRAF^V600E and RAS mutational status are not associated with prognosis in dMMR mCRC patients, in contrast to pMMR mCRC patients. Lynch syndrome is also not an independent prognostic factor for survival. These findings underline that prognostic factors of patients with dMMR mCRC are different of those with pMMR, which could be taken into consideration when prognosis is used for clinical decision‐making in dMMR mCRC patients and underline the complex heterogeneity of mCRC.