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Introduction. The ability of dextromethorphan to potentiate serotonin levels and lead to serotonin syndrome is well known but few case reports are published. The lack of published cases suggests therapeutic doses of these drugs are not enough to cause serotonin syndrome. We present two cases of serotonin syndrome associated with supra-therapeutic doses of dextromethorphan and therapeutic levels of a selective serotonin reuptake inhibitors (SSRI). Case Series. In case one, serum drug levels from admission revealed a dextromethorphan level of 950 ng mL (normal<5), escitalopram of 23 ng mL (normal<200), chlorpheniramine of 430 ng mL (normal<20) and undetectable levels of aripiprazole and benztropine. In case two, serum drug levels from admission revealed a dextromethorphan level of 2820 ng mL, sertraline of 12.5 ng mL (normal<200), and caffeine of 1.4 μg mL (normal≤ 9 μg mL). Discussion. To our knowledge, these are the first cases to use serum levels of dextromethorphan and a SSRI to confirm dextromethorphan-induced serotonin syndrome. Conclusion. Our cases suggest supra-therapeutic dextromethorphan doses with a therapeutic amount of a SSRI are required for serotonin syndrome. More work is needed to answer this question more completely.