Background: Platelet transfusion is utilized increasingly for traumatic brain injury (TBI) for the reversal of aspirin (ASA) therapy. Assessment of platelet inhibition and reversal by platelet transfusion after TBI has not been adequately characterized. Methods: A retrospective cohort analysis of TBI patients at a level I trauma center (January 2008-December 2009) was performed. The Aspirin Response Test (ART; VerifyNow) was used to assess platelet inhibition in TBI patients and guide platelet transfusion in patients with ASA-induced suppression. A follow-up ART was obtained after platelet administration. Primary endpoints were progression of intracranial hemorrhage on computed tomography, need for craniotomy, and mortality. Results: We analyzed 84 patients (median age, 78 [interquartile range, 64-86)]; 54% male). ASA use was documented in 36 (42%) patients. Initial ART indicated platelet dysfunction in 54 (64%) patients, including 42% of patients without a documented history of ASA use. Of the patients with a documented history of ASA, 2.4% had a normal ART. Of those with an initial ART of <550 ASA response units, 45 received platelets. Repeat ART demonstrated reversal of inhibition in 29 patients (64.4%). Initial responders to transfusion received a greater volume of platelets, suggesting a dose-response relationship. Logistic regression revealed a trend toward higher mortality in nonresponders to transfusion (P =.09). Receiver operating characteristic curve analysis revealed that ART results increased prediction of poor outcome compared with ASA history alone (area under the curve = 0.760 and 0.775, respectively). Conclusion: The ART should be used to better target and guide platelet transfusions in TBI patients with known or suspected ASA use history. Patients with occult platelet dysfunction can be identified, unnecessary platelet transfusions avoided, and the adequate volume of platelets administered to correct drug-induced dysfunction. A dose-response relationship between quantity of platelets transfused and reversal of ASA inhibition was observed.