To investigate the protein expression levels of cyclin-dependent kinase subunit 2 (CKS2) and the cluster of differentiation (CD) 47 in gastric cancer (GC) and their clinical significance. A total of 126 GC patients who underwent radical resection were selected as study subjects. Additionally, 32 patients with benign gastric tumour, 42 patients with low-grade intraepithelial neoplasia (LGIEN), and 49 patients with high-grade intraepithelial neoplasia (HGIEN) who underwent surgery were selected as the control groups. Immunohistochemistry was used to detect the expression of CKS2 and CD47 in surgical specimens. We statistically analysed the clinical significance of the expression of the two factors. (1) The positivity rates for CKS2 in benign gastric tumour tissue, LGIEN tissue, HGIEN tissue, and GC tissue gradually increased, that is, 6.3% (2/32), 30.9% (13/42), 38.8% (19/49), and 60.3% (76/126), respectively, and the positivity rates for CD47 were 18.8% (6/32), 38.1% (16/42), 46.9% (23/49), and 65.9% (83/126), respectively. (2) High expression of CKS2 and CD47 were associated with tumour diameter, Lauren classification, number of lymph node metastases, and TNM stage. In addition, the immunohistochemical scores for CKS2 and CD47 were positively correlated (r=.625, P=.000). (3) The median follow-up time of 126 patients was 46.5months, and the overall survival (OS) rate was 40.5% (51/126). Survival analysis showed that compared with that in the CKS2 (-) group, the OS rate for patients in the CKS2 (+) group was significantly worse and that compared with the CD47 (-) group, the CD47 (+) group had significantly worse OS (30.1% vs 60.5%, χ2 =15.67, P=.000). (4) The OS rates of CKS2 (+) CD47 (+) group, CKS2 (+) CD47 (-) group, CKS2 (-) CD47 (+) group, and CKS2 (-) CD47 (-) group were 20.0% (13/65), 58.3% (7/12), 57.1% (8/14), 65.7% (23/35), respectively, the prognosis of patients in CKS2 (+) CD47 (+) group was significantly poor. High expression levels of CKS2 and CD47 were closely related to the occurrence of GC and can be used as independent risk factors to assess the prognosis of patients.