Penetration of model beta-blockers, propranolol, oxprenolol, metaprolol, and nadolol, into dimyristoylphosphatidylcholine (DMPC) monolayers cast on a pH 7.4 phosphate buffer (mu = 0.155 adjusted with NaCl) at 25 degreesC was monitored using a film balance equipped with a Wilhelmy plate for measuring changes in surface pressure. Drug solution (pH 7.4) is injected below the surface of the monolayer. The difference in surface pressure, Delta pi, for each drug concentration added to the monolayer was measured at equilibrium. Delta pi increased with increasing drug concentration. Consistent with the relative lipophilicities, the Delta pi vs drug concentration slopes were as follows: propranolol > metaprolol > oxprenolol > nadolol. The intrinsic surface activity of the beta-blockers was also determined in the absence of the lipid. Differential scanning calorimetry (DSC) measurements were also made on DMPC bilayers in the above buffer. DMPC suspended in buffered drug solutions were scanned over a temperature range of 5 degrees to 40 degreesC at a scan rate of 0.091 degreesC/min. The DSC studies indicate that the DMPC thermotropic phase behavior is modulated by these compounds as follows: propranolol >> metaprolol congruent with oxprenolol > nadolol which agrees with reported partition coefficients as well as the above Delta pi observations. However, an accounting of the intrinsic surface activity of these compounds results in a lower than expected affinity for the DMPC monolayer.