Objectives: The aim of this study is to analyse the relationship between smoking and altitude mountain sickness in a cohort of travellers to 2500 metres above sea level (masl) or higher. Setting: Travel Health Clinic at the Hospital Universitari de Bellvitge, in Barcelona, Spain. Participants: A total of 302 adults seeking medical advice at the travel clinic, between July 2012 and August 2014, before travelling to 2500 masl or above, who agreed to participate in the study and to be contacted after the trip were included. Individuals who met the following criteria were excluded: younger than 18 years old, taking carbonic anhydrase inhibitors for chronic use, undergoing treatment with systemic corticosteroids and taking any medication that might prevent or treat altitude mountain sickness (AMS) prior to or during the trip. The majority of participants were women (n=156, 51.7%). The mean age was 37.7 years (SD 12.3). The studied cohort included 74 smokers (24.5%), 158 (52.3%) non-smokers and 70 (23.2%) ex-smokers. No statistical differences were observed between different sociodemographic characteristics, constitutional symptoms or drug use and smoking status. Outcomes: The main outcome was the development of AMS, which was defined according to the Lake Louise AMS criteria. Results: AMS, according to the Lake Louise score, was significantly lower in smokers; the value was 14.9%, 95% CI (6.8 to 23.0%) in smokers and 29.4%, 95% CI (23.5 to 35.3%) in non-smokers with an adjusted OR of 0.54, 95% CI (0.31 to 0.97) independent of gender, age and maximum altitude reached. Conclusions: These results suggest that smoking could reduce the risk of AMS in non-acclimated individuals. Further studies should be performed in larger cohorts of travellers to confirm these results. Despite the results, smoking must be strongly discouraged because it greatly increases the risk of cardiorespiratory diseases, cancer and other diseases.