Background: Females (F) have a lower incidence of CRC and carry a better overall prognosis than males(M). We explored the differences in the molecular profile of CRC as an explanation for the differences in the outcome. Methods: CRC cases submitted to Caris Life Sciences from 2015 to 2017 were analyzed. These cases were tested with next generation sequencing (NGS) of 592 genes and a panel of IHC and copy number variation assessment. Microsatellite instability (MSI) was evaluated with NGS for known MSI loci in the target regions. High Tumor mutational load (TML-H) was defined as ≥17 mutations/megabase. Results: Data from a total of 1768 CRC tumors (F: 859; M: 909) was available for analysis. The mean age at testing was similar between the two groups (F 59 vs. M 60 years). Tumor location was unknown in more than 40% of the cases. For those with known tumor location (1056) F had a higher rate in right sided than left sided and rectal tumors (51% vs. 47% vs. 40%, p = 0.006). Overall, F carried significantly lower frequency of mutation in APC (68% vs. 74%, p = 0.02), higher frequency of BRAF (11% vs. 6.6%, p = 0.003) and BRCA1 (2% vs. 0.6%, p = 0.007). PDL1 expression was higher in F (4.5% vs. 2.1%, p = 0.006) and MGMT expression was higher in M (63% vs. 56%, p = 0.04). There was no significant difference in the TML-H (F:6.4% vs. M:5.9%) and MSI-high (F:6.2% in vs M:4.8%). When primary (877) and metastatic tumors (838) were investigated separately, mutations in APC was higher in M primary tumors (74% vs. 68% p = 0.03) while not different in metastatic sites. On the contrary, BRCA1 mutations were higher in the metastatic sites for F (2% vs. 0.2%, p = 0.02). PD-L1 was higher in the primary tumor of F (5.2% vs. 1.8%, p = 0.008) and PD-1 on tumor infiltrating lymphocyte in metastatic tumors in F (48% vs. 30%, p = 0.01). Conclusions: The profile of female patients (higher rates of PDL1 in primary and PD1 in metastatic tumors) supports a higher degree of immune evasion. The differences in the profile of metastatic vs. primary sites may be due to the differences in the mechanism of metastasis in females vs. males and may have implications for PDX models.