We tested the hypothesis that, in humans, hyperthermic hyperpnea elicited in resting subjects differs from that elicited during submaximal, moderate intensity exercise. In the rest trial, esophageal temperature (T_es) was increased in 19 healthy male subjects using hot legs-only water immersion and a water-perfused suit; in the exercise trial, T_es was increased by prolonged submaximal cycling (50% V_O2peak) in the heat (35°C). Minute ventilation (V_E), ventilatory equivalent for V_O2 (V_E V_O2^-1) and V_CO2 (V_E V_CO2^-1), tidal volume (TV) and respiratory frequency (f_R) were plotted as functions of T_es. In the exercise trial, V_E increased linearly with increases in T_es (37.0-38.7) in all subjects, while in the rest trial, 14 of the 19 subjects showed a T_es threshold for hyperpnea (37.8±0.5°C). Above the threshold for hyperpnea, the slope of the regression line relating V_E and T_es was significantly greater for the rest trial than the exercise trial. Moreover, the slopes of the regression lines relating V_E V_O2^-1, V_E V_CO2^-1 and T_es were significantly greater in the rest trial than in the exercise trial. The increase in V_E reflected increases in both T_V and f_R in the rest trial, but only f_R in the exercise trial after an initial increase in ventilation due to T_V. Finally, the slope of the regression line relating T_es and T_V or f_R was significantly greater in the rest trial than the exercise trial. These findings indicate that hyperthermic hyperpnea does indeed differ depending upon whether one is at rest or exercising at submaximal, moderate intensity.