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First synthesized in 1970, propafenone is a frequently used 1C antiarrhythmic drug metabolized into two major metabolites, 5-hydroxypropafenone and norpropafenone. Paradoxically, fatal intoxication is rarely described, and only six cases have been reported in the literature. We report our experience with two patients found dead of self-inflicted poisoning where the propafenone blood concentration was very high (one concentration to our knowledge is one of the highest reported in the literature). At autopsy, no evidence of significant pathological disease were found. Propafenone was detected in blood by gas chromatography-mass spectrometry and by high-performance liquid chromatography using a diode-array detector, respectively, as propafenone artifact and propafenone. Blood propafenone concentrations were 4180 ng/mL and 9123 ng/mL. The literature regarding propafenone pharmacokinetic and intoxication is reviewed, and we discuss the low death rate attributed to this drug in contrast to its frequent use.