Mixed monolayers of cyclosporin with poly(isobutyl cyanoacrylate) nanoparticles containing Pluronic as the polymerizing agent exhibited marked deviation from ideal behavior. This deviation was increased by increasing the pH and decreased by raising the temperature, which suggests that it was largely due to ion-dipole and dipole-dipole interactions, though a contribution by hydrogen bonding between cyclosporin NH groups and poly(isobutyl cyanoacrylate) CO groups cannot be ruled out. The negative values of the molar excess free energy, entropy, and enthalpy of mixing, and the minima observed for monolayers with mole fractions of cyclosporin between 0.2 and 0.4, suggest the formation of a "complex" or well-defined surface structure of maximum stability favored by low enthalpy. The existence of such strong interactions between poly(isobutyl cyanoacrylate) nanoparticles and cyclosporin may have serious implications for the bioavailability of cyclosporin administered in such nanoparticles.