Transdermal delivery is preferable for some drugs to oral administration or intravenous injection. Macromolecules such as peptide drugs, however, little penetrate through the skin. In this paper, we have studied the effect of the molecular weight of penetrants on the diffusion across the skin, under the influence of the electric field applied. Since large molecular drugs used in this study hardly penetrated through the intact skin with the whole stratum corneum, the model drugs permeated through the viable skin without stratum corneum completely more than 100 times greater than through the intact skin. This finding implies that the stratum corneum is the major diffusional barrier. In addition, the diffusion coefficients of the compounds across viable skin were inversely proportional to the molecular weight with the exponent of 0.38 (D proportional to (M.W.)(-0.38)), suggesting a similar trend in the aqueous medium. The flux of vitamin B U (M.W. = 1.4 x 10(3)) increased appreciably during iontophoresis application, and the fluxes were proportional to the current density applied. However, FITC-Dextrans with the average molecular weight of 4.4 x 10(3) to 19 x 10(3) increased negligibly during iontophoresis, while skin pretreatment by iontophoresis appreciably increased the penetration. After the removal of the electric field, FITC-Dextrans continuously penetrated at a higher level.