There is an increasing body of evidence suggesting that altered vascular permeability may be an important component of the pathogenesis of acute mountain sickness (AMS). Vascular endothelial growth factor (VEGF) is a potent permeability factor subject to hypoxic regulation but its role in the pathogenesis of AMS is yet to be defined. We examined the relationship between plasma VEGF and AMS on ascent to high altitude and subsequent acclimatisation. Thirty-eight healthy lowlanders (median age 21, range 18-31) flew to La Paz, Bolivia (3650 m) on the Apex 2 research expedition. After 4-5 days acclimatisation, they ascended by vehicle over 90 min to the Chacaltaya laboratory (5200 m). We measured plasma VEGF in venous blood at sea level and at 6 h and 3 and 7 days at 5200 m. AMS was scored using the Lake Louise consensus system. Using serial measurement of plasma VEGF at 5200 m, following partial acclimatisation at 3650 m, we demonstrated a highly significant change in VEGF levels (P<0.0005) with a rise in VEGF in approximately 80% of subjects by day 7 at 5200 m. We found no evidence of an association between AMS and change in VEGF levels on ascent to either 3650 or 5200 m. We provide novel data of change in plasma VEGF levels during acclimatisation to high altitude, but our results do not support the hypothesis that circulating unbound VEGF is an important component of the pathogenesis of AMS.