UNLABELLED Exposure to altitudes >2500 m can result in acute mountain sickness (AMS), a mild and usually self-limiting condition. Research has attempted to identify factors associated with developing AMS without controlling important factors related to the ascent or collecting a comprehensive set of variables. OBJECTIVES The Antarctic Study of Altitude Physiology (ASAP) investigated variables associated with the development of AMS in adults experiencing rapid passive transport to altitude by airplane. DESIGN Our prospective observational trial collected data, including personal history, anthropometrics, vital signs, blood samples and pulmonary function, at sea level and at altitude. Statistical analysis utilised independent sample t tests to investigate between-group differences (p<0.05) and a forward, step-wise binary logisitic regression analysis was performed. PARTICIPANTS Of 248 eligible ASAP participants, those who did not use acetazolamide (N=98) were included in the present analysis. PRIMARY OUTCOME MEASURES The diagnosis of AMS using the Lake Louise Symptom Score. RESULTS Analysis of participants not using acetazolamide (n=90) found 30 participants developed AMS and 60 participants did not. Estimated plasma volume decreased significantly at altitude (p=0.025) in the AMS group as compared with the No AMS group while body weight did not change (p=0.125). Serum sodium (p=0.045) and low-density lipoprotein (LDL) (p=0.049) levels were higher in the No AMS group. A logistic regression analysis emphasised the contributions of LDL and eosinophil levels in the development of AMS. CONCLUSIONS These results suggest that the body water regulation and inflammation are key factors in AMS development when all other factors such as the level of physical exertion during ascent, the rate and magnitude of ascent and the use of acetazolamide are controlled.