Structure-activity relationships were sought for 73 enhancers of hydrocortisone permeation from propylene glycol across hairless mouse skin. Enhancers had chain lengths (CC) from 0 to 16 carbon atoms, 1 to 8 H-bonding atoms (HB), molecular weight 60 to 450, log P (calculated) −1.7 to 9.7 and log S (calculated) −7.8 to 0.7. These predictive properties were chosen because of their ready availability. Enhancement ratio (ER) was defined as hydrocortisone transferred after 24 h relative to control. Values for the ER ranged from 0.2 to 25.3. Multiple regression analysis failed to predict activity; ER values for the ‘good’ enhancers (ER>10) were underestimated. Simple guidelines suggested that high ER was associated with CC>12 and HB 2–5. This was refined by multivariate analysis to identify significant predictors. Discriminant analysis using CC, HB, and molecular weight correctly assigned 11 of the 12 ‘good’ enhancers (92%). The incorrectly assigned compound was a known, idiosyncratic Br compound. Seventeen of the 61 ‘poor’ enhancers (28%) were incorrectly assigned but four could be considered marginal (ER>8). The success of this simple approach in identifying potent enhancers suggested its potential in predicting novel enhancer activity.