The purpose of this project was to test the hypothesis that increases in muscle sympathetic nerve activity (MSNA) during an orthostatic challenge is attenuated in heat-stressed individuals. To accomplish this objective, MSNA was measured during graded lower body negative pressure (LBNP) in nine subjects under normothermic and heat-stressed conditions. Progressive LBNP was applied at -3, -6, -9, -12, -15, -18, -21, and -40 mmHg for 2 min per stage. Whole body heating caused significant increases in sublingual temperature, skin blood flow, sweat rate, heart rate, and MSNA (all P < 0.05) but not in mean arterial blood pressure (P > 0.05). Progressive LBNP induced significant increases in MSNA in both thermal conditions. However, during the heat stress trial, increases in MSNA at LBNP levels higher than -9 mmHg were greater compared with during the same LBNP levels in normothermia (all P < 0.05). These data suggest that the increase in MSNA to orthostatic stress is not attenuated but rather accentuated in heat-stressed humans.