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INTRODUCTION Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with adverse cardiovascular outcomes and reportedly overused in American-style football (ASF). However, assessment of ASF NSAID use in the context of cardiovascular risk has not been performed. We sought to characterize NSAID use patterns and the association with cardiovascular risk in a diverse cohort of high school and collegiate ASF athletes. METHODS A total of 226 ASF athletes, 60 endurance athletes, and 63 nonathletic controls were studied pre- and postseason with echocardiography, vascular applanation tonometry, and clinical data assessment. Qualitative NSAID use throughout the season was recorded at postseason. RESULTS ASF athletes gained weight (Δ0.86 ± 3.9 kg, P < 0.001), increased systolic blood pressure (SBP, Δ3.1 ± 12 mm Hg, P < 0.001) and pulse wave velocity (Δ0.2 ± 0.6 m·s, P < 0.001), and decreased E' (Δ-1.4 ± 2.8 cm·s, P < 0.001) across one athletic season. Seventy-seven percent (n = 173) of ASF athletes reported that sport-specific NSAID use began in middle school. ASF NSAID use was more frequent with "weekly" (n = 42.19%) and "daily" (n = 32.14%) use compared with endurance athletes (P < 0.001) and controls (P = 0.02). ASF NSAID use increased in parallel with postseason SBP and weights. "Daily" ASF NSAID users demonstrated the highest postseason SBP (137 ± 13 vs 128 ± 13 mm Hg, P = 0.002) and weight (109.0 ± 18.6 vs 95.8 ± 20.5 kg, P = 0.002) compared with "never/rare" users. Adjusting for player position, SBP, pulse wave velocity, and E', increased weight (odds ratio = 1.04, 95% confidence interval = 1.0-1.08, P = 0.037) was associated with more frequent NSAID use. CONCLUSIONS Habitual NSAID use commonly begins during adolescence, before full physical maturation, and is associated with cardiovascular risk, particularly increased weight, in ASF athletes. NSAID use frequency should be considered when risk stratifying high-risk ASF athletes.