Background: Alpha-fetoprotein-positive gastric cancer (AFPGC) is a subtype of gastric cancer that is rare in clinical practice and extremely malignant. Malignant tumors are often associated with hemorrhage, thrombosis, and even disseminated intravascular coagulation (DIC). The D-dimer test is used as a sensitive index in the diagnosis of DIC and fresh thrombosis in malignant tumors. Therefore, this study aims to investigate the relationship between D-dimer values and the clinical characteristics and prognosis of patients with serum AFPGC (AFP ⩾ 15 μg/L) patients. Methods: Overall, 120 healthy subjects and 120 AFP-negative gastric cancer (AFP < 15μg/L) patients from May 2017 to July 2018 at the Shanxi Cancer Hospital served as the control group in this retrospective cohort study. Additionally, 120 patients with pretreatment advanced serum AFP were chosen to analyze clinicopathologic features and factors that affect prognosis. The predictor was the D-dimer, and the outcome variable was overall survival (OS). Other variables included age, sex, tumor site, T-stage, distant metastasis, and preoperative serum tumor biomarkers. Differences in OS rate were analyzed by GraphPad Prism 9.2.0.332. The Cox regression model was used for univariate and multivariate analysis. Results: In comparison to AFP-negative gastric cancer, we discovered that D-dimer had a meaningfully higher presentation in patients with AFPGC ( P < .001). Based on D-dimer median levels, the AFPGC patients were divided into two groups, including 39 patients with low D-dimer (<1000 ng/mL) and 81 patients with high D-dimer (⩾1000 ng/mL). The variables, including T-stage, distant metastasis, and expression of HER2, were associated with the value of D-dimer. The D-dimer levels were weakly related to the levels of tumor markers. The differences in AFPGC patients, with an OS rate of 30.76% for patients with low D-dimer (<1000) and 12.30% with high D-dimer (⩾1000; P = .0027), were statistically significant. Cox multivariate analysis of various parameters indicated that T-stage, distant metastasis, vascular embolism, level of D-dimer, and tumor biomarkers of AFP were independent risk factors for survival. Conclusion: Serum D-dimer levels may be a valuable indicator for predicting AFPGC metastasis and progression.