Eighteen peptides were examined for penetration across the blood-brain barrier (BBB) in rats. Iodinated peptides were injected via the carotid artery and 5 sec later the rats were decapitated. The results were expressed as a brain to blood ratio. The results showed that small amounts of most peptides enter the brain. The octanol coefficient, a measurement of lipophilicity, was a good predictor of penetration for most peptides. The low molecular weight, N-tyrosinated peptides (leucine-enkephalin, methionine enkephalin, N-Tyr-MIF-1, and N-Tyr-FMRF), that have been shown to be transported out of the brain by a saturable, carrier-mediated system, had much lower penetration rates than those predicted by their octanol coefficients. Molecular weight, percent of unbound peptide, total charge, net charge, and absolute charge were not good predictors of peptide penetration. Pretreatment of the rats with IP aluminum, which has been suggested to increase lipophilic permeability of the BBB, enhanced passage of 15 of the 18 peptides but not radioiodinated serum albumin or radioactive red blood cells. Thus, of the various physicochemical characteristics of peptides tested here, lipophilicity was most important in determining penetration of peptides across the BBB. However, the existence of one class of peptides that deviates from this trend (those of low molecular weight with an N-tyrosine) and the variability among the remaining peptides suggests that other, unidentified factors may be important in the prediction of peptide penetration across the BBB.