Abstract <p>Cancer is associated with arterial and venous thrombotic events (ATE/VTE). Platelet FcγRIIa (pFCG) impacts platelet activation that contributes to ATE/VTE. Recurrent myocardial infarction (MI) and death are predicted by pFCG in patients with MI. Crosstalk between platelets and malignant cells that may promote cell invasion and cancer progression is mediated by pFCG. The objective is to determine whether pFCG (high vs. low) identifies cancer patients at greater risk of thrombosis and death. Ambulatory patients with cancer (<i>n</i> = 219) initiating cancer directed therapy were enrolled in a prospective translational study. The pFCG test was performed at study initiation and used flow cytometry to quantify mean fluorescence intensity that was translated to molecules of FCG/platelet. Outcomes of VTE/ATE and all cause death were abstracted from the Electronic Health Record at least 6 months after enrollment. Hazard ratios (HR) were analyzed with Kaplan-Meier analysis. Risk of the composite endpoint (ATE/VTE/death) was increased in patients with high pFCG (HR 1.9, 95% confidence interval [CI] 1.1–3.2, <i>p</i> = 0.02). A consistent non-significant trend for increased composite of ATE/VTE was associated with high pFCG (HR 1.7, 95% CI 0.8–3.3, <i>p</i> = 0.14). High pFCG identified patients at greater risk of all-cause death (HR 2.5, 95% CI 1.3-5.0, <i>p</i> = 0.009). Among patients who died (<i>n</i> = 50), ATE/VTE was a cause of death in 4 (8%) and temporally not associated with death in 19 (38%). The pFCG test identifies cancer patients at greater risk of death and could predict risk of thromboembolism. Additional studies are warranted to evaluate this novel biomarker of risk.</p> <p><i>Clinical trial registration:</i> NCT05240508.</p> Graphical abstract <p>This study was performed to determine whether platelet FcɣRIIa identifies cancer patients at greater risk of thrombosis and death. Additional studies are warranted to evaluate this novel biomarker of risk.</p> <p></p>