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To examine effects of exercise in the heat and fluid intake on erythrocyte sickling and neutrophil activation in carriers of sickle cell trait (HbAS).Six African American men (2 HbAS; 42% HbS, 4 HbAA; 20.7 ± 0.8 years; 87.4 ± 9.6 kg) participated in 2 randomized sessions (separate days) each consisting of 45 minutes of brisk walking (treadmill) in a hot (33°C) environment.Subjects consumed no fluids or fluid for 3 hours prior to (ad libitum) and during (1.02 L) testing.Core temperature, heart rate, and perceived exertion were measured. Forearm venous blood was analyzed for percent erythrocyte sickling and plasma myeloperoxidase.Time-averaged heart rate (126.6 ± 5.7 vs. 146.7 ± 5.9 bpm; P = 0.02) and core temperature (37.6 ± 0.1 vs. 38.1 ± 0.1°C; P < 0.05) responses were lower during fluid versus no fluid, with no statistically significant difference in perceived exertion (12.3 ± 0.5 vs. 13.6 ± 0.4; P = 0.06). Erythrocyte sickling progressively increased (to 3.5%–5.5%) for HbAS carriers during no fluid exercise only. No sickling was detected in HbAA subjects. Plasma myeloperoxidase responses to exercise were greater (P = 0.03) in HbAS versus HbAA.Fluid ingestion at a rate sufficient to offset a body weight deficit can effectively reduce erythrocyte sickling during exercise in the heat.