Background: Mutational status in colorectal cancer (CRC) impacts response to EGFR inhibition, prognosis, and may affect response to chemoradiation. It is unclear if obesity or other clinical characteristics, including smoking and diabetes, increases the predilection for certain genotypes. The purpose of the following study was to explore the relationship between clinical factors, codon-specific mutations and overall survival (OS). Methods: Metastatic colorectal cancer patients were retrospectively analyzed; clinical characteristics including smoking, diabetes, and body mass index (BMI) were extracted from medical records. Genotyping was performed for > 150 mutations across 15 commonly mutated cancer genes including NRAS, KRAS, PIK3CA, BRAF, and PTEN as part of their clinical management and recorded. Logistic regression was used to establish associations between clinical characteristics and genotypes. Results: 394 metastatic CRC patients were identified. Median age was 58 (range 25-89). 219 (56%) were male. 202 (51%) were non-smokers. 61 had diabetes. 272 patients had a BMI ≥ 25. 136 patients had KRAS mutations, the most common of which was G12D (37%). Diabetes was associated with a higher incidence of KRAS (odds ratio [OR] 1.9 95% CI 1.1-1.3; p = 0.02) and PIK3CA mutations (OR 2.4 95% CI 1.1-5.0; p = 0.02), but not OS. KRAS mutations were not significantly associated with BMI ≥ 25 nor OS. BRAF mutations were significantly associated with poorer OS (hazard ratio [HR] 1.9 95% CI 1.3-2.7; p < 0.001). Current smokers were more likely to have CTNNB1 mutations (OR 11.3 95% CI 1.5-83.2; p = 0.02) and G12D KRAS mutations (OR 5.6 95% CI 1.0-30.3). Current smokers were less likely to have BMI ≥ 25 (OR 0.44; p = 0.02). Patients with BMI ≤ 18.5 have an association with poor OS (HR 2.6 95% CI 1.1-6.4; p = 0.03), although this needs to be corroborated with a larger sample size. Conclusions: A statistically significant association was found between diabetes and KRAS and PIK3CA mutations. The association of BRAF mutations and decreased overall survival was significant, concordant with previous reports. Smokers were more likely to harbor G12D KRAS mutations, and low BMI (≤ 18.5) trended toward poorer overall survival.