ABSTRACT: Monte Carlo simulations were used to describe the interaction of peripheral and integral proteins with lipids in terms of heat capacity profiles and protein distribution. They were based on a two-state model for the lipid, representing the lipid state as being either gel or fluid. The interaction between neighboring lipids has been taken into account through an unlike nearest neighbor free energy term w, which is a measure of the cooperativity of the lipid transition. Lipid/protein interaction was considered using the experimental observation that the transition midpoints of lipid membranes are shifted upon protein binding, a thermodynamic consequence of different binding constants of protein with fluid or gel lipids. The difference of the binding free energies was used as an additional parameter to describe lipid-protein interaction. The heat capacity profiles of lipid/protein complexes could be well described for both peripheral and integral proteins. Binding of proteins results in a shift and an asymmetric broadening of the melting profile. The model results in a coexistence of gel and fluid lipid domains in the proximity of the thermotropic transition. As a consequence bound peripheral proteins aggregate in the temperature range of the lipid transition. Integral proteins induce calorimetric melting curves qualitatively different from that of peripheral proteins and aggregate in either gel or liquid crystalline lipid phase. The results presented here are in good agreement with calorimetric experiments on lipid-protein complexes and have implementations for the functional control of proteins.