The surface pressure-surface area (π-A) isotherms of cyclosporin A (CyA) and the whole range of mole fractions of CyA with dipalmitoylphosphatidylcholine (DPPC) have been determined. The isotherm of pure CyA rises gradually and undergoes a transition at about 15 dyn/cm. CyA forms nonideal films at low surface pressures based on analysis of the compressibility (πA/kT) as a function of surface pressure. The limiting area is calculated to be about 130 Å2/molecule, which corresponds to a smaller area/amino acid than has been observed with larger, linear polypeptides. The attractive interactions were comparable to medium chain fatty acids spread at the air/water interface. The extent of hysteresis was measured by repeated compression and expansion of a monolayer of CyA. The equilibrium spreading pressure of CyA was found to be about 30 dyn/ cm, which together with the observed hysteresis indicates that a combination of instability as well as molecular rearrangement occurs with monolayers of CyA above 15 dyn/cm. Comparison of the weighted average molecular areas of mixtures of CyA with DPPC reveals that deviations from simple additivity occur at both low and high mole fractions of CyA at a surface pressure below the liquid expanded to liquid condensed phase transition. The results suggest that the introduction of the second component causes a disruption in the association leading to the nonideal behavior. The additivity of the area / molecules at equal mole fractions of CyA may indicate the presence of a compensatory mechanism in the packing of the lipid and protein.