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This study aimed to investigate the biomarkers and underlying pathogenesis of ischemic stroke in patients with gastric cancer (GC).Patients with active gastric cancer who had experienced acute ischemic stroke without conventional vascular risk factors (gastric cancer-related stroke [GCS] group) and visited The First Affiliated Hospital of Guangxi Medical University and First Affiliated Hospital of Sun Yat-sen University from January 2003 to December 2016 were retrospectively enrolled. The patients’ clinical features and laboratory findings were compared with those of age-, sex-, and disease progression-matched patients with GC without ischemic stroke (GC group) who had been admitted to the same hospital during the same period (GCS:GC ratio = 1:2).Among the 9166 patients diagnosed with GC, 70 had experienced a cerebral infarction and were enrolled in this study. Among them, 53 (75.71%) harbored multiple lesions in multiple vascular territories. Notably, patients in the GCS group exhibited significant increases in the D-dimer and cancer antigen 125 (CA125) levels and platelet-to-neutrophil ratio (PNR), compared to their counterparts in the GC group. A multiple logistic regression analysis identified all 3 factors as independent risk factors for cerebral infarction in patients with GC (D-dimer, odds ratio [OR] = 1.006 per 1 ng/mL increase, 95% confidence interval [CI], 1.004–1.009, P = .000; CA125, OR = 1.016 per 1 U/mL increase, 95% CI, 1.005–1.027, P = .005; PNR, OR = 1.025 per 1 point increase, 95% CI: 1.003–1.048, P = .023).Elevated plasma D-dimer and CA125 levels and an increased PNR might affect the occurrence of GC-related ischemic stroke and could therefore serve as potential biomarkers.