BACKGROUND: Although few retrospective studies of high altitude have reported that obesity might be associated with the development of acute mountain sickness (AMS), this association has not been studied prospectively. OBJECTIVE: To determine whether obesity is associated with the development of AMS. DESIGN: Obese and nonobese men were compared at a simulated altitude of 3658 m (12 000 ft). SETTING: 24 hours in a hypobaric environmental chamber. PARTICIPANTS: 9 obese and 10 nonobese men. MEASUREMENTS: Percentage body fat (by hydrostatic weighing), Lake Louise AMS score, and Sao2 level (by pulse oximetry) were measured. RESULTS: Average AMS scores increased more rapidly with time spent at simulated high altitudes for obese men than for nonobese men (P < 0.001). The response of Sao2 with exposure differed between nonobese and obese men. After 24 hours in the altitude chamber, seven obese men (78%) and four nonobese men (40%) had AMS scores of 4 or more. CONCLUSION: Obesity seems to be associated with the development of AMS, which may be partly related to greater nocturnal desaturation with altitude exposure.