Ultrasound is frequently used in physical medicine. In a preliminary study, we demonstrated that the thermal effect of ultrasound was the principal explanation for the increase in the diffusion rate of digoxin. The aim of this study was to investigate further the phonophoresis of three drugs with a cooling thermostat, thus suppressing the thermal effect of ultrasound. Sonication was carried out at 1.5 W/cm 2 , 1.1 MHz for 20 min. We used modified Franz diffusion cells adapted for sonication. During sonication the temperature in the donor compartment was continuously monitored and maintained at 31°C by the cooling coil. Diffusion of the tritiated drugs (hydrocortisone, mannitol, oestradiol) across hairless mouse and whole human skin was determined by liquid scintillation counting for up to 24 h, and the steady-state flux was determined. No enhancement in steady-state diffusion rates was observed for the three drugs in comparison with controls. The thermal effect of ultrasound seems to be the main factor which enhances percutaneous administration under the conditions used in physical medicine.