Today, NPS are increasingly being related to post-mortem cases, and this problem drastically intensifies as a result of the New Synthetic Opioids (NSOs) surge. Among NSOs, carfentanil (CaF) is the most potent fentanyl analogue and was central to a large number of NSOs-related fatalities in North America, as well as in UE, since 2016. In this worrisome context, this manuscript reports the first CaF-related fatality occurred in France. A 41-years-old man was found dead with a syringe planted under his tongue. This man has a psychiatric follow-up for opiate addiction and his recent medical history included intoxication with fentanyl derivatives. Toxicological investigations of post-mortem samples (blood, urine and hair), and syringe were requested. CaF (with several other psychoactive drugs at non-toxic level) was detected in biological samples and in syringe residue using LC-HRMS, and quantified using LC-MS/MS in blood, urine and hair (from proximal to distal hair section – 3cm length each) at 4.20, 0.40μg/L and 54/114/166pg/mg, respectively. The relatively high post-mortem CaF blood concentration together with the absence of metabolite (especially NorCaF) suggests a sudden death of the victim immediately following a significant CaF dose intake (presumably injected) that can explain the decease.