This study aims to identify the proportion of high altitude travellers who use acetazolamide in a way that is likely to be safe, and prevent high altitude illness; and, to identify, assess, and understand the factors that affect acute mountain sickness prophylaxis usage. The study area was the Everest area of Nepal. The qualitative component involved 20 one-to-one in-depth semi-structured interviews. Analysis was conducted using thematic analysis. The quantitative component involved conducting a questionnaire on 50 guides, and 300 trekkers at high altitude. Data was analysed using descriptive statistics. Guides had a poor knowledge of prophylactic medication. 25% of trekkers used acetazolamide. 3.3% of the trekkers used acetazolamide at a total dose of 250mg daily, initiated it 1-2 days before high altitude, and did not miss a dose. Poor knowledge amongst trekkers and guides was the main determinant of such poor uptake and inappropriate usage. Trekkers' knowledge was primarily obtained from guide books and healthcare professionals. Poor knowledge amongst trekkers and guides determined poor uptake, and inappropriate prophylaxis usage amongst trekkers. We believe that to improve prophylaxis uptake and use, and hence reduce trekkers' morbidity and mortality, policy makers must deliver trekker-targeted educational interventions in Nepal.