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SUMMARYPurpose: The use of alternate methods for antiepileptic drug delivery has been proposed as a putative strategy to enhance efficacy and tolerability of chronic pharmacotherapy. Intranasal administration is of specific interest based on its general potential for targeted central nervous system delivery. Therefore we analyzed whether intranasal administration of phenobarbital may render a valuable therapeutic approach. In conclusion, intranasal administration of phenobarbital in rats is associated with efficient brain penetration rates allowing to achieve therapeutic concentrations. Based on these data, intranasal phenobarbital administration seems to render a suitable alternate delivery route for this antiepileptic drug, which should be further evaluated.