BACKGROUND Prehospital medication is a reality, and the role of these therapies must be explored to assess their validity, especially for acute respiratory diseases, which are usually associated with increased morbidity. The aim of this study was to examine the association of prehospital medication use with mortality in patients with acute respiratory disease. METHODS: A prospective, multicenter, emergency medical service (EMS) delivery cohort study was carried out in adults with unselected respiratory diseases managed by EMS who were transferred to the emergency department. From January 1, 2019, to October 31, 2023, six advanced life support units, thirty-eight basic life support units, and four hospitals in Spain participated in the study. Demographic data, vital signs, use of mechanical ventilation, prehospital respiratory diagnosis, and prehospital medication were collected. The primary outcome was 30-day in-hospital mortality. RESULTS: A total of 961 patients were included, with a mortality rate of 17.5% (168 patients). Age, an increasing number of comorbidities, the use of invasive mechanical ventilation (IMV), the use of major analgesics, hypnotics, and bicarbonate were risk factors. In contrast, elevated systolic blood pressure and Glasgow Coma Scale scores were found to be protective factors against mortality. The predictive capacity of the model reached an area under the curve (AUC) of 0.857 (95% confidence interval [95% CI] 0.827-0.888). CONCLUSION: Our data revealed that IMV, major analgesics, hypnotics and bicarbonate administration were associated with elevated mortality. Adding prehospital drug therapy information to demographic variables and vital signs could improve EMS decision-making, allowing a better characterization of patients at risk of clinical worsening.