Most reports of adverse effects of dextromethorphan (DM), such as CNS depression, involve accidental overdose or voluntary ingestion. DM is metabolized to dextrorphan by the polymorphic isoenzyme CYP2D6. So far, there has been no report of adverse clinical consequence of this genetic polymorphism involving DM. We report the death of a toddler after a therapeutic dose of DM given for cough. A 22 month old male of oriental origin received 3 mg of DM once at 9:00 AM and again at 10:00 PM and was found dead at 4:35 AM. Postmortem examination was unremarkable except for signs of early bronchopneumonia (bacterial and viral cultures were negative). DM and dextrorphan blood concentrations taken from the heart cavity were 500 ng/mL and 200 ng/mL, respectively. General drug screen was otherwise negative. Intentional or unintentional overdose was extremely unlikely by history. Despite the DM level almost 100-fold higher than expected with a therapeutic dose, the dextrorphan level was 4-fold lower than expected. A dextromethorphan/dextrorphan ratio of 2.5 is characteristic of a slow CYP2D6 metabolizer. To exclude postmortem drug redistribution as an alternative explanation for the high DM level, a study was performed in rats. In rats sacrificed 2.5 hours after dosing (n=12), DM blood concentrations taken 8 to 24 hours postmortem increased only 2 to 15-fold. In rats sacrificed 0.5 hour after dosing (n=14), there was no change. Extensive postmortem redistribution could not explain the observed high DM level. Therefore, a slow CYP2D6 metabolizer phenotype is the most likely explanation for the almost 100-fold increase in blood concentration observed. We conclude that the combination of early signs of bronchopneumonia and very high DM concentration, caused by slow CYP2D6 metabolizer phenotype, could explain the death of the child, when one considers the CNS depression caused by DM at very high levels.