A drug-related fatality involving ocfentanil (OcF) is reported in this work. OcF is a potent synthetic opioid, structurally analogue of fentanyl, abused as a new psychoactive substance in the recreational drug scene. A 39-year-old man with a history of heroin addiction was found dead in the cellar of his house. Typical paraphernalia of drug abuse (lighter, foundation cream and a small syringe) and a resealable plastic zipper bag containing several hundred milligrams of a brown powder were found close to the dead body. A crime scene investigation and legal autopsy was ordered. While no anatomic cause of death was observed, toxicological analysis revealed the presence of OcF in post mortem specimens and in the brown powder. An ultra-performance liquid chromatography tandem mass spectrometry (UHPLC–MS/MS) based method was developed and validated for OcF identification and quantitation. The following concentrations of OcF were reported: 36,4 ng/mL in peripheral blood, 49,8 ng/mL in cardiac blood, 67,9 ng/mL in urine, 365 ng/mL in bile, 75,5 ng/g in kidney, 106 ng/g in liver, 108 ng/g in lung and 72,0 ng/g in brain. The medical examiner reported that the cause of death was opioid intoxication and the manner of death was accident.