A B S T R A C T Phloretin dramatically increases cation conductances and decreasesanion conductances of membranes treated with ion carriers (nonactin, valinomycin, carbonyl-cyanide-m-chiorophenylhydrazone [CCCP], and Hg(CnFs)2) or lipophilic ions (tetraphenylarsonium [TPhAs +] and tetraphenylborate [TPhB-]). For example, on phosphatidylethanolamine membranes, 10 -4 M phloretin increases K+-nonactin and TPhAs + conductances and decreases CCCP-and TPhBconductances 10a-fold; on lecithin:cholesterol membranes, it increases K+-nonactin conductance 1on-fold and decreases CCCP-conductance 10n-fold. Similar effects are obtained with p-and m-nitrophenol at 10 -2 M. These effects are produced by the un-ionized form of phioretin and the nitrophenols. We believe that phloretin, which possesses a large dipole moment, adsorbs and orients at the membrane surface to introduce a dipole potential of opposite polarity to the preexisting positive one, thus increasing the partition coefficient of cations into the membrane interior and decreasing the partition coefficient of anions. (Phloretin may also increase the fluidity of cholesterol-containing membranes; this is manifested by its two-to threefold increase in nonelectrolyte permeability and its asymmetrical effect on cation and anion conductances in cholesterol-containing membranes.) It is possible that phloretin's inhibition of chloride, urea, and glucose transport in biological membranes results from the effects of these intense interfacial dipole fields on the translocator(s) of these molecules.