Colorectal cancer (CRC) is a malignancy with a high propensity for returning after treatment. Ongoing investigations are exploring effective therapeutic avenues for individuals diagnosed with CRC. This study set out to compare the detection of programmed death-ligand 1 (PD-L1) and anaplastic lymphoma kinase (ALK) across stage III and IV CRC cases, and to assess the clinicopathological relevance of their detection. A sample set of 169 stage III and IV CRC tissues underwent immunohistochemical testing for ALK (D5F3) and PD-L1 (SP142 and SP263) on formalin-fixed paraffin-embedded material. Clinicopathological parameters were collected from medical charts and by reassessing hematoxylin and eosin slides. Detection of PD-L1 SP142 and PD-L1 SP263 was recorded in 17.8% and 28.4% of CRC cases, respectively. ALK D5F3 detection was documented in 4 instances. A significant relationship emerged between PD-L1 SP142 detection and both tumor location and serum carcinoembryonic antigen (CEA) concentration. PD-L1 SP263 detection was tied to serum tumor marker levels and the presence of tumor-infiltrating lymphocytes. Univariate analysis revealed an association between PD-L1 detection and reduced overall survival in CRC patients. In multivariate analysis, PD-L1 SP263 detection emerged as an independent marker of shorter survival. PD-L1 detection was associated with indicators of poor clinical outcome, including shortened survival time. Subsequent studies are warranted to elucidate the pathways