Objective <p>To investigate the differential expression of the c-Myc proto-oncogene in intestinal-type gastric cancer (ITGC), diffuse-type gastric cancer (DTGC), and gastric mucosal intestinal metaplasia (IM), and to assess its clinical significance.</p> Methods <p>A total of 262 archived paraffin-embedded gastric tissue specimens were obtained from Putuo Hospital, Shanghai University of Traditional Chinese Medicine, collected between January 2016 and December 2024. The specimens included 30 samples of normal gastric mucosa (NM), 180 of IM (subclassified as mild [<i>n</i> = 60], moderate [<i>n</i> = 60], and severe [<i>n</i> = 60]), 30 of ITGC, and 22 of DTGC. C-Myc protein expression was evaluated by immunohistochemistry using the EnVision™ system and categorized as low (&lt; 15% positive cells), moderate (15%-40%), or high (≥ 40%). Statistical analyses were performed using the Mantel-Haenszel trend test, Kruskal-Wallis test, Duncan’s multiple comparison test, and chi-square test.</p> Results <p>C-Myc expression differed significantly among gastric mucosal lesions (<i>P</i> &lt; 0.001). Moderate IM exhibited higher c-Myc expression than NM, DTGC, and severe IM (<i>P</i> &lt; 0.05). High c-Myc expression was more frequent in ITGC (26.67%) than in DTGC (4.55%), NM, or severe IM (<i>P</i> &lt; 0.05). Among IM subtypes, types I and II IM demonstrated elevated c-Myc expression compared with NM and DTGC (<i>P</i> &lt; 0.05), while type III IM exhibited lower expression levels. Patients with ITGC were significantly older than those in other cohorts (<i>P</i> &lt; 0.05). Female predominance was observed in the NM group, whereas male predominance was observed in the ITGC group.</p> Conclusion <p>C-Myc expression shows stage-specific heterogeneity during gastric carcinogenesis. The significantly higher c-Myc expression in ITGC compared with DTGC supports the molecular basis of the Lauren classification and may aid in the development of targeted therapeutic strategies.</p>