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Previous research demonstrated that Methadone Maintenance Programs (MMP) and Methadone Maintenance Treatment/Therapy (MMT) could significantly reduce the mortality risk. However, in current forensic practice, methadone ingestion can still directly or indirectly be involved in fatalities. The objectives of this study were twofold. Firstly, referring to the wide range of blood levels reported in methadone-related fatalities, we aimed to provide insight into the interpretation of a quantitative post-mortem blood concentration. Secondly, to examine and discuss possible causes, mechanisms and manners of death. During a 30-year-period, all medico-legal files at the Department of Forensic Medicine (Ghent University) were searched through, to investigate whether methadone was involved in the fatal outcome. A significant increase in the methadone-related fatalities was found since 1995, which has also been noticed in other studies. In our study (n=48), the most frequent cause of death was intoxication: only one was due to a pure methadone intoxication, whereas in all other fatal intoxications, a poly-drug intoxication was found. In this study, cardiopulmonary failure, induced by depression of the vital centres in the brainstem, was--as expected--the most important mechanism of death. When we considered the post-mortem blood levels in our study group, we observed a wide range, namely between 0.10 and 4.13 microg/ml (median: 0.54 microg/ml, mean: 0.81 microg/ml, SD: 0.14). This was in line with previous reports, although the extreme values differed. We conclude that the interpretation of post-mortem methadone blood levels is still hazardous due to e.g. difficulties to assess the individual tolerance level, the variety of surviving periods after ingestion, interfering post-mortem redistribution and the combined ingestion of methadone with other drugs. Therefore, a close collaboration between the forensic pathologist and toxicologist is recommended in order to provide a well-grounded conclusion.