Respiratory depression and fatalities have been attributed to ethanol/buprenorphine (BUP) combination in drug addicts maintained with BUP/naloxone or BUP alone. The exact mechanisms of the ethanol/BUP interaction and the contribution to the toxicity of norbuprenorphine (NBUP), the main BUP metabolite with respiratory depressant properties are unknown. We investigated the sedative and plethsymographic effects resulting from the co-administration of intragastric ethanol (3 g/kg) and intravenous BUP (30 mg/kg) in Sprague–Dawley rats. We determined the whole blood pharmacokinetics of ethanol (using gas chromatography coupled to mass spectrometry), BUP and its metabolites (using liquid chromatography coupled to tandem mass spectrometry) and investigated the mechanisms of drug–drug interactions in the presence or absence of naloxone (7.5 mg/kg). Ethanol/BUP and ethanol/BUP/naloxone combinations significantly deepened sedation in comparison to BUP alone (P < .01) and BUP/naloxone (P < .05), respectively. Ethanol/BUP combination significantly increased the inspiratory time and decreased the minute volume in comparison to BUP alone (P < .01 and P < .01, respectively) and ethanol/BUP/naloxone (P < .05 and P < .01, respectively). Neither naloxone nor flumazenil reversed ethanol/BUP-induced sedation and respiratory depression. In the presence of ethanol, the area under the BUP concentration–time curve was significantly decreased (P < .05), BUP volume of distribution increased (P < .05) and the metabolic ratios of NBUP and norbuprenorphine-3-glucuronide increased (P < .01). In conclusion, the ethanol/BUP combination results in marked sedation and respiratory depression in the rat, prevented but not reversed by naloxone. Ethanol/BUP interactions are mainly pharmacokinetic resulting in increased NBUP production. Despite the non-reversal by naloxone and flumazenil of the effects attributed to the ethanol/BUP combination, protection provided by naloxone suggests an additional pharmacodynamic interaction.