As the mechanism involved in the serious adverse effects associated with phenylpropanolamine (PPA) has not yet been clarified, and as PPA in usual cases is not being ingested without other drugs combination, the aim of this study was to characterize the possibility of pharmacokinetic interactions between PPA and most often combined drugs existing in the same dosage. The pharmacokinetics of PPA in rat brain and blood were evaluated when administered alone (group I), combined with caffeine (group II), combined with chlorpheniramine (group III), combined with both caffeine and chlorpheniramine (group IV) and finally when existed in one of the available OTC products (group V). This product contains multiple ingredients of PPA, caffeine and chlorpheniramine. In brain the pharmacokinetic parameters of PPA were significantly affected with the combined administration of caffeine and/or chlorpheniramine. The single intraperitoneal administration of caffeine (5 mg/kg) with PPA (2.5 mg/kg) to rats caused 1.6-fold increase in the AUC of PPA in brain compared to the single administration of PPA, and was comparable to the 1.5-fold increase caused by chlorpheniramine (0.4 mg/kg). The multiple combinations caused an increase in the AUC by 1.9-fold, which is comparable to the increase in the AUC of PPA obtained from the OTC product (2.2-fold). On the other hand, there was no significant difference in the pharmacokinetics of PPA in blood between the groups except for the C(max) of PPA in groups I and IV. The observed adverse effects associated with PPA use could be related to the significant increase in its levels in the brain.