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American football athletes are frequently hypohydrated before and during activity. Hypohydration increases the risk of exertional sickling in student-athletes with sickle cell trait (SCT). The authors examined weight charts from the 2010/2011 to 2018/2019 seasons at one Division I institution to determine if differences in percentage body mass losses (%BML) exist between those with and without SCT. Seventeen student-athletes with SCT and 17 matched-controls were included. A Bonferroni correction was applied to account for multiple comparisons (0.05/8), resulting in p < .006 considered significant. There was a significant difference for %BML between groups (SCT: 0.84 ± 0.65% vs. control: 1.21 ± 0.71%; p = .002) but not for the number of days %BML exceeded 2% (SCT: 0 ± 1 vs. control: 1 ± 1; p = .016). Implementation of proper hydration strategies minimized %BML in athletes with SCT, decreasing the risk of hypohydration and exertional sickling. The same strategies ensured all players remained below threshold to optimize performance and reduce heat illness risk.