The effects of trifluoperazine and another phenothiazine, chlorpromazine, on p-aminohippurate (PAH) transport in rat kidney cortical slices were examined. Increasing concentrations of trifluoperazine up to 0.1 mM progressively stimulated PAH accumulation in the slices, but a higher concentration of trifluoperazine (0.3 mM) did not cause stimulation. Chlorpromazine also had biphasic effects on PAH accumulation. Both drugs had biphasic effects on hypotonic hemolysis as well, i.e., they protected the erythrocytes at low concentrations, and lysed them at high ones. The effect of trifluoperazine and chlorpromazine on the kinetics of PAH accumulation was to increase Vmax, while the apparent Km remained constant. The efflux of PAH from the slices was significantly decreased by these antipsychotic drugs. The stimulation by trifluoperazine of PAH accumulation was blocked by tetraethylammonium. These results suggest that the antipsychotic drug, when taken up or adsorbed by the slices, stimulates PAH accumulation and that such stimulation may arise at least in part because of membrane stabilization.