Acute acetaminophen (ACT) ingestion has been reported to reduce thermal strain during cycling in the heat. In this study, nine active participants ingested 20 mg of ACT per kg of total body mass (ACT) or a placebo (PLA), 60 min prior to cycling at a fixed rate of metabolic heat production (ACT: 8.3 ± 0.3 W/kg; PLA: 8.5 ± 0.5 W/kg), which was equivalent to 55 ± 6% VO2max , for 60 min at 34.5 ± 0.1 °C, 52 ± 1% relative humidity. Resting rectal temperature (Tre ; ACT: 36.70 ± 0.17 °C; PLA: 36.80 ± 0.16 °C, P = 0.24), esophageal temperature (Tes ; ACT: 36.54 ± 0.22 °C; PLA: 36.61 ± 0.17 °C, P = 0.50) and mean skin temperature (Tsk ; ACT: 34.00 ± 0.14 °C; PLA: 33.96 ± 0.20 °C, P = 0.70) were all similar among conditions. At end-exercise, no differences in ΔTre (ACT: 1.12 ± 0.15 °C; PLA: 1.11 ± 0.21 °C, P = 0.92), ΔTes (ACT: 0.90 ± 0.28 °C; PLA: 0.88 ± 0.23 °C, P = 0.84), ΔTsk (ACT: 0.80 ± 0.39 °C; PLA: 0.70 ± 0.46 °C, P = 0.63), mean local sweat rate (ACT: 1.02 ± 0.15 mg/cm(2) /min; PLA: 1.02 ± 0.13 mg/cm(2) /min, P = 0.98) and whole-body sweat loss (ACT: 663 ± 83 g; PLA: 663 ± 77 g, P = 0.995) were evident. Furthermore, ratings of perceived exertion and thermal sensation and thermal comfort were not different between ACT and PLA conditions. In conclusion, ACT ingested 60 min prior to moderate intensity exercise in hot-humid conditions does not alter physiologic thermoregulatory control nor perceived strain.