Background Patients with heart failure, reduced ejection fraction (HFrEF) and sinus rhythm have a heightened risk of stroke. Whether anticoagulation benefits these patients is uncertain. In this posthoc analysis of COMMANDER-HF trial we evaluated how a previously validated risk model consisting of three variables (history of prior stroke, insulin-treated diabetes, and NTproBNP) would perform, compared to plasma D-dimer, for stroke prediction and estimation of the benefit of low-dose rivaroxaban. Methods and results Stroke risk and treatment effect were computed across risk score and plasma D-dimer tertiles. Risk score was available in 2,928 (58%) of the COMMANDER-HF population. Over a median follow-up of 512 (342-747) days, 60 patients experienced a stroke (14.6 per 1000 patient-years). The risk model did not identify patients at higher risk of stroke and showed a low overall prognostic performance (C-index=0.53). The effect of rivaroxaban on stroke was homogeneous across risk score tertiles (P-interaction=0.67). Among patients in whom the risk score was estimated, D-dimer was available in 2,343 (80%). D-dimer had an acceptable performance for stroke prediction (C-index=0.66) and higher plasma D-dimer concentrations were associated with higher rates of stroke (i.e. T3 vs. T1, HR 3.65 [95%CI 1.59-8.39], P=0.002). Treatment with lowdose rivaroxaban reduced the incidence of stroke in patients at highest risk by D-dimer levels (i.e. >515 ng/mL; HR 0.42 [95%CI 0.18-0.95], P-interaction=0.074), without any safety concern. Conclusions In our analysis, plasma D-dimer concentrations performed better than a previously described three-variable risk score for stroke prediction in patients with HFrEF, a recent clinical worsening and sinus rhythm as enrolled in the COMMANDER-HF trial. In these patients, a raised plasma D-dimer concentration identified patients who might benefit most from rivaroxaban.