Topically applied compounds can penetrate directly into deeper underlying tissues. In this report, an attempt has been made to establish structure-deep tissue penetration relationships for a variety of solutes with diverse physicochemical properties. Stepwise multiple linear regression analysis was performed with the concentration in the immediately overlying tissue, the solute molecular size and the octanol/water partition coefficient as independent variables. During the initial period of direct penetration, the concentration of any solute in a given tissue was dependent on the concentration in the preceding tissue. The presence of molecular weight and lipophilicity terms as independent variables improved the regressions for some tissues. The solute concentration in the deeper tissues of sacrificed animals was higher for the smaller solutes. Due to the dominance of solute clearance by blood perfusing the tissues, the dependence of solute concentrations in anesthetized animal tissues on size was less than observed for sacrificed animals. The predictions from these regression analyses yielded predictions similar to those based on a physiological pharmacokinetic model. However, only about 50% of the data was explained by both models. Based on the preliminary qualitative and quantitative analysis, deep tissue penetration of solutes after application, as aqueous solutions, to the epidermis is greater for smaller solutes with adequate lipophilicity.