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Study Objective: Aspirin (ASA) has demonstrated inconsistent results in primary prevention of cardiovascular disease (CVD). Guidelines are also inconsistent in the recommendation of routine ASA use for primary prevention of CVD, but advocate dosing as a "one-size-fits-all" approach.Design: An intention-to-treat, double-blind, randomized, controlled, clinical trial comparing three treatment arms of ASA 81, 325, and 500 mg daily dosed for 14 days were evenly randomized across the dosing categories to measure the impact of dosing by body mass index (BMI) (20-24.9, 25-29.9, ≥30 kg/m 2 ) on ASA anti-platelet effects.Setting: University Ambulatory Clinic.Patients: Healthy volunteers defined as individuals who were medication free without acute or chronic significant health problems.Intervention: Change in ASA reactivity unit (ARU), salicylate levels, and thromboxane B2 (TxB2) levels were measured across BMI dosing categories and time.Main Results: Fifty-four participants with a mean (±SD) age of 34.4 ± 10.9 years (M:F; 23:31) completed the study. Baseline ARU and TxB2 levels were not significantly different between obese and non-obese individuals. BMI was not a predictor of platelet inhibition. There was no interaction between gender and platelet activation at baseline or following ASA treatment. ASA 81 mg was associated with a lower ARU response (approximate 50% lower response) than either the 325-mg or the 500-mg doses of ASA. TxB2 and salicylate levels exhibited lower trends at 81 mg compared with higher doses. Conclusions:In healthy male and female participants administered ASA for 14 days, obesity is not associated with increased basal platelet activation or ASA resistance.ASA 81 mg was significantly less effective in reducing platelet aggregation compared with ASA 325 and 500 mg, independent of BMI.