Acute mountain sickness (AMS) is common at high altitude (HA) and is associated with a relative failure of the natriuresis and diuresis that occurs at HA. The role of brain natriuretic peptide (BNP) in this context has not been thoroughly investigated. We aimed to clarify if BNP rises in response to exercise at HA and if so whether this is related to markers of acclimatization. Thirty-two healthy subjects had assessments of BNP, aldosterone and markers of HA acclimatization (as assessed by the AMS-C score of the environmental symptom questionnaire (EQ12) and lake louise questionnaire) made following exertion at sea-level (SL), 3400, 4300 and 5150 m. Data were analysed in the 23 subjects who did not consume drugs known to affect acclimatization. BNP (pg/ml, mean±S.E.M.) was significantly higher at 5150 m versus the lower altitudes (P<0.001 for all): 7.1±1; 6.1±0.3; 6.8±0.9 and 17.7±5.1 at sea-level; 3400; 4300 and 5150 m respectively. In those that showed no BNP response at 5150 m (n=4) versus those that did demonstrate a BNP response (n=19) there was a significant difference in lake louise (LL) acute mountain sickness scores at 5150 m on day 10 of the expedition (mean LL score 0.75 vs 3.3, P=0.034) and day 11 (mean LL score 0 vs 3.3, P=0.003). Acute mountain sickness is defined by a LL score >3. This is the first report to demonstrate a significant rise in BNP at HA. A BNP response at 5150 m is associated with a greater likelihood of suffering AMS.