BACKGROUND: Benzodiazepines can exacerbate opioid-induced respiratory depression by furthering the decrease in central respiratory drive and causing loss of upper airway patency potentially leading to airway obstruction. This study aimed to determine if co-administration of benzodiazepines and opioids significantly decreases hypercapnic ventilation compared with opioids alone. METHODS: We conducted a randomised, double-blind, four-period crossover trial in 20 healthy participants to assess whether i.v. midazolam (0.0375 mg kg RESULTS: Midazolam administered with oxycodone, compared with oxycodone alone, did not significantly decrease minute ventilation at an end-tidal Pco CONCLUSIONS: Midazolam co-administered with oxycodone did not decrease hypercapnic ventilation, compared with oxycodone alone, but did affect tidal volume, ventilatory frequency, and resting end-tidal Pco CLINICAL TRIAL REGISTRATION: NCT04310579.