Divers are at enhanced risk of hypothermia, due to the independent action of the inspired inert gases on thermoregulation. Thus, narcosis induced by acute (≤2h) exposure to either hyperbaric nitrogen, or normobaric nitrous oxide (N2O) impairs shivering thermogenesis and accelerates body core cooling. Animal-based studies, however, have indicated that repeated and sustained N2O administration may prevent the N2O-evoked hypometabolism. We therefore examined the effects of prolonged intermittent exposure to 30% N2O on human thermoeffector plasticity in response to moderate cold. Fourteen men participated in two ~12-h sessions, during which they performed sequentially three 120-min immersions (CWI) in 20˚C water, separated by 120-min rewarming. During CWIs, subjects were breathing either normal air, or a normoxic gas mixture containing 30% N2O. Rectal and skin temperatures, metabolic heat production (via indirect calorimetry), finger and forearm cutaneous vascular conductance (CVC; laser-Doppler fluxmetry/mean arterial pressure), and thermal sensation and comfort were monitored. N2O aggravated the drop in rectal temperature (P = 0.01), especially during the first (by ~0.3°C) and third (by ~0.4°C) CWIs. N2O invariably blunted the cold-induced elevation of metabolic heat production by ~22-25% (P < 0.001). During the initial ~30 min of the first and second CWIs, N2O attenuated the cold-induced drop in finger (P ≤ 0.001), but not in forearm CVC. N2O alleviated the sensation of coldness and thermal discomfort throughout (P < 0.001). Thus, present results demonstrate that, regardless of the cumulative duration of gas exposure, a subanasthetic dose of N2O depresses human thermoregulatory functions, and precipitates the development of hypothermia.