A major obstacle to successful cancer chemotherapy is the development of multidrug resistance (MDR) characterized by the overexpression of the drug transporter P-glycoprotein and the enhanced cellular efflux of many anticancer drugs. The identification and use of agents that reverse the MDR phenotype or drug-resistant tumors could provide an adjuvant to conventional cancer chemotherapy that would significantly enhance treatment efficacy. Several derivatives of acrivastine and a structurally-related benzyl piperazine were used in the present study to establish the utility of structure-activity and in vitro analyses to identify compounds that are effective at sensitizing MDR tumors in vivo. Of the seven compounds evaluated, 5 were identified by structure-activity analyses as inhibitors of P-glycoprotein, 1 was identified as a possible inhibitor, and 1 was deemed a non-interactor. In vitro analyses indicated that all seven compounds could inhibit P-glycoprotein; however, the compound identified by structure-activity analyses as a non-interactor was least potent. In vivo experimentation revealed that the more potent P-glycoprotein inhibitors, as determined by either structure-activity analyses or in vitro testing, also sensitized multidrug-resistant tumor masses implanted into athymic nude mice to treatment with vinblastine; though, efficacy was limited by host toxicity. Results from this study corroborate previously-established relationships between chemical structure and P-glycoprotein inhibition. Results further demonstrate that P-glycoprotein inhibitory potency, as established by structure-activity or in vitro analyses, provides insight into the ability of the agent to sensitize drug-resistant tumors in vivo.