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Simple Summary: Colorectal cancer (CRC) is one of the most prevalent malignant neoplasms worldwide, responsible for over 900,000 deaths yearly. As the immunotherapies targeting the PD-1/PD-L1 axis in CRC are effective only in microsatellite unstable tumours, which are 15% of all CRC cases, new targets of immune evasion are still needed. B7H3 has been reported to mediate immune escape and promote tumour progression in numerous malignancies, but it has yet to be fully elucidated in CRC. The study investigates whether B7H3 expression is related to MSI/MSS status, tumour infiltrating lymphocytes and cytokine composition in CRC. We found that B7H3 expression is upregulated in CRC tumours and independent of MSI/MSS status. B7H3 correlated positively with cytokines supporting tumour growth and was associated with M2-macrophage polarization. Additionally, TCGA analysis showed that high B7H3 expression in CRC tumours is related to decreased survival in CRC patients. Our findings provide a novel insight into B7H3's role in CRC immunity. The study aimed to assess the expression of B7H3 concerning clinicopathological and histological parameters, including MSI/MSS status, CD-8 cells, tumour-infiltrating lymphocytes (TILs), budding, TNM scale and grading. Moreover, we analyzed the B7H3-related pathways using available online datasets and the immunological context of B7H3 expression, through the 48-cytokine screening panel of cancer tissues homogenates, immunogenic features and immune composition. The study included 158 patients diagnosed with CRC. To assess B7H3 levels, we performed an immunohistochemistry method (IHC) and enzyme-linked immunosorbent assay (ELISA). To elucidate the immune composition of colorectal cancer, we performed the Bio-Plex Pro Human 48-cytokine panel. To study biological characteristics of B7H3, we used online databases. Expression of B7H3 was upregulated in CRC tumour tissues in comparison to adjacent noncancerous margin tissues. The concentrations of B7H3 in tumours were positively associated with T parameter of patients and negatively with tumour-infiltrating lymphocytes score. Additionally, Principal Component Analysis showed that B7H3 expression in tumours correlated positively with cytokines associated with M2-macrophages and protumour growth factors. The expression of B7H3 in tumours was independent of MSI/MSS status. These findings will improve our understanding of B7H3 role in colorectal cancer immunity. Our study suggests that B7-H3 is a promising potential target for cancer therapy. Further studies must clarify the mechanisms of B7H3 overexpression and its therapeutic importance in colorectal cancer. [ABSTRACT FROM AUTHOR]