Background Colorectal cancer leads to peritoneal metastases (CRPM) in 10% of cases. Cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) improves survival. Primary tumor location and abnormalities in RAS , BRAF , and mismatch repair/microsatellite stability (MMR/MSI) may affect post-CRS-HIPEC survival, but studies have not been consistent. We estimated the effects of primary tumor site and genomic alterations on post-CRS-HIPEC survival. Methods This retrospective cohort study included CRS-HIPEC cases for CRPM at a high-volume center from 2001 to 2020. Next-generation sequencing and microsatellite testing defined the RAS , BRAF , and MMR/MSI genotypes. Adjusted effects of tumor sidedness and genomics on survival were evaluated using a multivariable Cox proportional hazards model. We analyzed these variables’ effects on progression-free survival and the effects of immune checkpoint-inhibitors. Results A total of 250 patients underwent CRS-HIPEC with testing for RAS , BRAF , and MMR/MSI; 50.8% of patients were RAS -mutated, 12.4% were BRAF -mutated, and 6.8% were deficient-MMR/MSI-high (dMMR/MSI-H). Genomic alterations predominated in right-sided cancers. After adjustment for comorbidities and oncological and perioperative variables, rectal origin hazard ratio (HR) 1.9, p  = 0.01, RAS mutation (HR 1.6, p  = 0.01), and BRAF mutation (HR 1.7, p  = 0.05) were associated with worse survival. RAS mutation was also associated with shorter progression-free survival (HR 1.6, p  = 0.01 at 6 months post-operatively), and dMMR/MSI-H status was associated with superior survival (HR 0.3, p  = 0.01 at 2 years). dMMR/MSI-H patients receiving immune checkpoint-inhibitors trended toward superior survival. Conclusions Rectal origin, RAS mutations, and BRAF mutations are each associated with poorer survival after CRS-HIPEC for CRPM. Patients with CRPM and dMMR/MSI-H status have superior survival. Further research should evaluate benefits of immune checkpoint-inhibitors in this subgroup.