A series of 48 propafenone-type modulators of multidrug resistance was synthesized and their P-glycoprotein inhibitory activity was measured using the daunomycin efflux assay. Both a Free-Wilson and a combined Hansch/Free-Wilson analysis were performed using log P, partial log P and molar refraction values as Hansch descriptors. The results of the Free-Wilson analysis show that modifications on the central aromatic ring generally influence pharmacological activity, whereby in almost all cases a decrease in MDR-modulating potency is observed (Q2cv = 0.66). The combined approach results in equations with remarkably higher predictive power (Q2cv = 0.83), specifically molar refractivity shows high significance in all equations derived. This indicates that polar interactions also contribute to protein binding.