Exertional heat stress increases gastrointestinal barrier permeability and risk of exertional heatstroke (EHS) via a TLR4-mediated inflammatory pathway. Curcumin has been shown to inhibit TLR4 signaling in vitro but has not been examined in a human exertional heat stress model. PURPOSE: This work investigated the effect of 3d of 500mg/d dietary curcumin supplementation on the cellular and systemic responses to exertional heat stress in non-heat acclimated humans. METHODS: Subjects (N=6) ran (65%VO2max) for 60min inside an environmental chamber (37°C/26%RH) two times (CURCUMIN/PLACEBO). Core temperature (Tc), heart rate (HR), and physiological strain index (PSI) were measured throughout exercise. Peripheral blood mononuclear cells (PBMC) were isolated from blood samples that were taken before (PRE), after (POST), 1hr (1-POST), and 4hrs after (4-POST) exercise. The protein content of markers along the TLR4 signaling pathway (TLR4, MyD88, pNFKB, NFKB) and indicators of cellular energy status (SIRT1 & p-AMPK) were determined with Western Blot. Group differences were determined with 2-Way (Condition x Time) RM ANOVAs. RESULTS: Under CURCUMIN, Tc rose less (0.23±0.15°C; p<0.01) and both HR and PSI were lower from 45-60min of exercise (HR: 9±2 bpm, PSI: 12±1%; p< 0.05). In PBMC, the ratio of pNFKB to NFKB at 1-POST was increased by 64% in PLACEBO and 51% in CURCUMIN (p=0.05). Intriguingly, TLR4 was reduced at 1POST in both conditions (PLACEBO: -28%, CURCUMIN: -17%; p=0.05), as were pAMPK (PLACEBO: -62%, CURCUMIN: -57%; p<0.01) and SIRT1 (PLACEBO: -61%, CURCUMIN: -48%; p=0.02). CONCLUSIONS: Despite robust improvements in systemic responses to exertional heat stress under CURCUMIN, there was no difference in the protein expression profile of PBMC that were collected under CURCUMIN and PLACEBO conditions. However, in both conditions we did note a significant elevation in pNFKB:NFKB at 1-POST, which (ironically) coincided with a significant reduction in TLR4 (but not MyD88). At present, our working hypothesis is that pAMPK and SIRT1 were downregulated in an effort to maintain the pro-inflammatory capacity of PBMC during this “open window”, an effect that has not previously been described in PBMC collected under exertional heat stress conditions.