Background: Tumor sidedness is a prognostic factor and predictive parameter for EGFR monoclonal antibody (mAb) treatment in mCRC. Sidedness is believed to be a surrogate for genomic differences. This study aimed to evaluate genomics vs. tumor sidedness in anticipating outcomes in mCRC. Methods: We included patients (pts) with microsatellite stable mCRC tested by Foundation Medicine tissue comprehensive genomic profiling assay. Patient data was obtained by the US-based de-identified Flatiron Health-Foundation Medicine real-world clinico-genomic database (FH-FMI CGDB), originating from approximately 280 US cancer clinics (1/2011–3/2023). Genomic alterations (GA) in 324 genes were compared between right and left side tumors using Fisher’s exact test, adjusted for multiple comparisons. Real-world progression-free survival (rwPFS) and overall survival (rwOS) were compared by Cox proportional hazard models adjusted for prognostic features in pts receiving 1^st line chemotherapy (chemo) + EGFR mAb or bevacizumab (bev). Multivariable analyses including prognostic features, sidedness and GA were performed. Comparisons of the explanatory power of genomics vs. sidedness were performed by the likelihood ratio test (LRT). Results: 3845mCRC pts (2584 left and 1261 right) were included. GA in APC, TP53, ARID1A, and FBXW7 were more prevalent in left side, while GA in BRAF, KRAS, AMER1A, PIK3CA, RNF43, BCOR, PTEN, SMAD4, MAP2K1, and BCOR in right side. 2109 pts received chemo + EGFR mAb or bev. Multivariable analyses identified BRAF, KRAS, MAP2K1, and APC as independently associated with outcomes. Pts were classified as having GA in RAS pathway (RASalt: KRAS/NRAS, BRAF, or MAP2K1), APC (APCalt), both RAS pathway and APC (APC/RASalt), and none. RASalt group had less favorable outcomes while APCalt group had more favorable outcomes, regardless of treatment received and sidedness. LRT indicated that when genomics was added to the sidedness evaluation, there was an improvement in outcome prediction (p<0.001), but not when sidedness was added to genomics. Conclusions: Tumor genomics better explains differences in outcomes than sidedness in 1^st line treatment in mCRC.