Background: Specifically, stomach cancer ranks as the fifth leading cause of cancer morbidity and mortality worldwide. Early-stage detection significantly improves survival rates, with over 90% of patients diagnosed at stages I and II living beyond five years. To improve the early detection of gastric cancer, it is necessary to complement the conventional method of endoscopic examination with biomarker analysis. We aimed to compare biomarkers such as pepsinogen C (PGC), matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), and the cell proliferation marker Ki-67 with immunohistochemical analysis. Purpose: A comparative study and evaluation of biomarkers for the early detection of gastric cancer. Materials and Methods: The study was conducted using a retrospective cohort design. Research ethics issues were discussed at the meeting of the Medical Ethics Control Committee of the Ministry of Health on October 13, 2023, and permission to start the research was obtained (Resolution No. 23/051). The information was gathered based on the criteria for K29.3, K29.4, K31, and C1 diagnoses according to the international ICD 10 classification, and participants were selected accordingly. Proteins such as PGC, MMP2, MMP9, and Ki-67 were examined using a tissue microarray kit and evaluated through immunohistochemical analysis. Results: Negative gastric tumor markers PGC, Ki-67, MMP2 and MMP9 were evaluated by immunohistochemical analysis. The mean PGC protein staining values were 6.20±2.61 for chronic superficial gastritis, 5.45±2.47 for atrophic gastritis, 3.61±2.0 for metaplasia, and 3.31±1.75 for gastric cancer, with statistically significant differences between the groups (P<0.001). The mean Ki-67 protein staining values were 0.1 ± 0.4 for chronic superficial gastritis, 0.33 ± 0.55 for atrophic gastritis, 0.09 ± 0.39 for metaplasia, and 2.62 ± 0.78 for gastric cancer, also showing statistically significant differences (P<0.001). The mean MMP2 and MMP9 protein staining values were 0.2±0.76 and 1.2±2.04, respectively, for chronic superficial gastritis; 0.28±0.52 and 3.28±2.82 for atrophic gastritis; 0.35±1.04 and 1.12±1.45 for metaplasia; and 1.38±2.11 and 5.29±2.51 for gastric cancer, with all differences being statistically significant (P<0.001). Conclusion PGC protein, a negative tumor marker, decreases during the transition from a gastric cancer precursor to cancer. MMP2 protein, a marker of cell migration and metastasis, has little diagnostic value, while the expression of MMP9 and the Ki 67 are highly effective in gastric cancer. Immunohistochemical analysis of endoscopic biopsy tissue to detect the negative tumor marker PGC, the positive marker Ki-67, and MMP9 can be used for early detection of gastric cancer.