The aim of the present study was to determine whether there are any clinicopathological or prognostic differences between patients with alpha-fetoprotein-secreting gastric carcinoma (AFP-SGC) and non-AFP-SGC. Pathological parameters, clinical parameters, and treatment efficacy were compared in patients with AFP-SGC and non-AFP-SGC. In total, 362 patients (53 with AFP-SGC and 309 with non-AFP-SGC) were included in the present study. Patients with AFP-SGC had significantly higher levels of lymphovascular invasion, perineural invasion (PNI), rate of liver metastasis, and stage IV cancer compared with patients with non-AFP-SGC (P<0.05). The median overall survival (OS) rate was 12.6 months in the AFP-SGC group, and 22.1 months in the non-AFP-SGC group (P<0.001). The median OS and disease free survival (DFS) of patients with stage I-III AFP-SGC were 28.1 and 13.4 months, respectively, whereas for patients with non-AFP-SGC, the OS and DFS were 45.3 and 38.0 months, respectively (P=0.01; P=0.02). The median OS for the stage IV AFP-SGC and non-AFP-SGC groups was 9.3 and 11.5 months, respectively (P=0.14). Multivariate analysis of the entire patient group revealed that the Eastern Cooperative Oncology Group (ECOG) performance score of >= 2, lymph node involvement, presence of PNI, high levels of carcino-embryonic antigen, and distant metastasis were significantly correlated with OS. The lymph node involvement, ECOG performance score of >= 2, AFP-SGC type, and weight loss at diagnosis were also significant factors influencing the DFS in the stage I-III group. In conclusion, patients with AFP-SGC had more aggressive clinicopathological features and biological behavior with an increased tendency of liver metastasis compared with patients with non-AFP-SGC. In the near future, AFP may become an important surrogate marker to manage therapies of patients with gastric cancer.