Background: Whole transcriptome (WT) analysis of primary colorectal cancer (pCRC) has shown that the tumor microenvironment (TME) plays a critical role in disease progression and response to treatment. Colorectal cancer liver metastases (CRCLM) bear many genetic similarities to primary tumors, however differences in the microenvironment could effect drug response. Since 80% of metastatic CRC patients have liver metastases there is a critical need for further molecular analysis of CRCLM. Methods: Using a novel method to identify aberrant activity of signaling pathways, continuous scores (called pathway cluster scores, PCS) were derived from subsets of Hallmark gene sets of MSigDB. PCS scores that were prognostic in CRCLM were considered relevant to disease progression. Combined studies of such scores in CRCLM and pCRC were used to explore differing effects of the colon and liver TMEs. Analyses were performed on published WT datasets of pCRC (4 cohorts, n = 2,978) and CRCLM (3 cohorts, n = 498). Immune cell infiltration levels were estimated with Immunedeconv. Results: The most significantly prognostic PCS score in CRCLM cohort GSE159216 (n = 171) was one derived from a cluster of 28 KRAS signaling genes, called K-score (p = .0004). Subtypes K+ (good prognosis) and K- (poor prognosis) denote samples with K-score above, respectively below, the median. Gene set enrichment analysis showed that in all CRCLM cohorts, K- was enriched versus (v) K+ in proliferation-related pathways, e.g. E2F signaling and DNA Repair, while K+ was enriched v K- in multiple immune system pathways. In both CRCLM cohorts, K+ was enriched v K- in infiltration of neutrophils and CD4+ T cells, while infiltration levels of CD8+ T cell were not significantly different between K+ and K-. The T cell homing chemokines CXCL12, CCL19, CCL21 were elevated in K+ v K-. The aforementioned molecular features of K+ and K- also held in all pCRC cohorts; however in these cohorts, K+ was also enriched v K- in B cell and M2 macrophage infiltration. Also, in pCRC expression of the B cell attractor CXCL13 and biomarkers for tertiary lymphoid structures (TLS) were significantly elevated in K+ v K-. Of note, TLS have been associated with response to immune checkpoint inhibitors in multiple cancer types. In addition, in 18 pairs of matching pCRC and CRCLM samples (GSE49355), K-scores of pCRC samples were significantly correlated to K-scores of the matching CRCLM samples (p = .01). Chemokine expression levels differed in matching pairs: mean expression of CXCL12 was significantly higher in CRCLM than pCRC, while mean expression of CXCL13 was significantly higher in pCRC than CRCLM. Conclusions: In the study cohorts, K- tumors in both pCRC and CRCLM, were proliferative and lacked inflammation. However, while both pCRC and CRCLM K+ tumors were inflamed and enriched with CD4+ T cells, only pCRC K+ tumors were likely to contain TLS.