A relationship between stratum corneum reservoir function and percutaneous absorption has been established in the hairless rat. Two hundred nanomoles of 10 substances that have a wide range of chemical structures were topically applied for 30 min and the total body distribution was measured after 96 h. The quantity of substance present in the stratum corneum reservoir after 30-min application was measured by liquid scintillation counting after tape-stripping the treated area. A linear relationship exists between the quantity of substance in this reservoir x(nmol X cm-2) and the total amount of radioactivity distributed in the body and excreta y(nmol X cm-2) after 96 h. The relationship is given by: y = 1.644 X x - 0.536 (r = 0.998, p less than 0.001). Apart from the steroids, 80-95% of the compounds were excreted in the urine; and with the exception of thiourea, this elimination was rapid, especially for mannitol and benzoic acid. We confirmed that in terms of penetration there is a factor of 50 between benzoic acid (best) and dexamethasone (worst). Thus the quantity of substance penetrating through intact rat skin can be predicted by measuring the horny layer concentration. The animal data reported here should be verified in humans.