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Background: Multiple cerebral territory infarcts of undetermined origin are typically attributed to cardioembolism; and most frequently atrial fibrillation. However the significance of three territory involvement in association with malignancy is under-recognized. Objective: To highlight the “Three Territory Sign” (bilateral anterior and the posterior circulation DWI lesions), as a radiographic marker of stroke due to malignancy. Methods: We conducted a retrospective analysis of patients at our institution from Jan 2014-Jan 2016 who suffered an acute ischemic stroke with MRI-DWI. We identified all ischemic strokes of undetermined etiology in patients with known malignancy (60 patients) and patients with stroke, atrial fibrillation and no malignancy (167 patients). Patients with both atrial fibrillation and malignancy were excluded. All DWI images were reviewed for 3, 2, and 1 territory lesions. Fisher Exact tests were used to identify statistical significance between the two groups. Statistical significance was set at 0.05. Results: There was a significant association between both cohorts (malignancy vs. atrial fibrillation) and the number of territory infarcts found. While the number of 1 {71.6% (n=43) vs. 79% (n=132)} and 2 territory infarcts {10.0% (n=6) vs. 17. 4% (n=29)} were similar between the two groups, 3 territory infarcts were > 5 times more frequent in malignancy as compared to atrial fibrillation {18.3% (n=11) vs. 3.5% (n=6)} ( p < 0.002 ). Post-hoc pairwise comparisons using the Bonferroni correction for multiple tests support that the 3 territory pattern differs from both 1 territory ( p=0.0033 ) and 2 territory ( p =0.0037 ) patterns. Conclusion: Cerebral territory infarctions involving the bilateral anterior and posterior circulation are 5 times more frequent in malignancy-related ischemic stroke than atrial fibrillation. The “Three territory sign” is a robust marker of malignancy-related stroke and should prompt evaluation for malignancy after exclusion of other known causes.