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Abstract Background Acute Mountain Sickness (AMS) is a pathophysiologic process that occurs in non-acclimated susceptible individuals rapidly ascending to high-altitude. Barometric pressure falls at high altitude and it translates to a decreased partial pressure of alveolar oxygen (PAO2) and arterial oxygen (PaO2). A gradual staged ascent with sufficient acclimatization can prevent AMS but emergent circumstances requiring exposure to rapid atmospheric pressure changes – such as for climbers, disaster or rescue team procedures, and military operations – establishes a need for effective prophylactic medications. This systematic review and meta-analysis aim to analyze the incidence of AMS during emergent ascent of non-acclimatized individuals receiving inhaled budesonide compared to placebo. Methods This current meta-analysis was conducted according to the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. We searched PubMed, Google Scholar and Embase for relevant studies. The efficacy of budesonide in reducing incidence of AMS was evaluated by calculating the pooled ORs and 95% CIs. The efficacy of budesonide in maintaining hemoglobin-oxygen saturation was evaluated by calculating standard mean difference (SMD) and 95% confidence intervals. Results We found that at high altitude, inhaled budesonide was effective in reducing the incidence of mild AMS [OR: 0.37; 95% CI, 0.14 to 0.9, p = 0.042] but was ineffective in reducing the incidence of severe AMS [OR: 0.46; 95% CI, 0.14 to 1.41, p = 0.17]. Inhaled budesonide was also effective in maintaining SpO2 (SMD: 0.47; 95% CI, 0.09 to 0.84, p = 0.014) at high altitude. However, it was not effective in maintaining or improving pulmonary function at high altitude. Systematic-review found no adverse effects of budesoide in the dose used for prophylaxis of AMS. Conclusions Our systematic review showed that prophylactic inhaled budesonide is effective in preventing mild AMS during emergency ascent but not effective in preventing severe AMS. Though statistically significant, authors recommend caution in interpretation of data and questions for further well designed randomized studies to evaluate the role of budesonide in prophylaxis of AMS during an emergent ascent.