We used direct calorimetry and respirometry to measure the total rate of heat loss (Qsigma) and of oxygen consumption (VO2) in guinea pigs in 1-atm (0.1 MPa) air and at 10-60 atm in either heliox (98% He, 2% O2) or hydrox (98% H2, 2% O2). Our objective was to determine if the physiological responses to these two gas mixtures were different and, if so, whether the differences were attributable to the thermal characteristics of the gases alone or were confounded by additional mechanisms. At 10-40 atm, Qsigma and VO2 were not significantly different in the two gas mixtures, whereas at 60 atm, Qsigma and VO2 were significantly higher in heliox than in hydrox. The VO2/Qsigma ratio suggested that the animals were not in thermal equilibrium in hyperbaria. Based solely on the differing thermal properties of the gas mixtures, a mathematical model predicted a Qsigma that was higher in hydrox than in heliox at all pressures. Two plausible explanations are suggested: one is an adaptive lowering of the surface temperature as a physiological response of the animal to the thermally more stressful hydrox environment, and the other is related to the narcotic suppression of the animal's activity by hydrox.