We compare the binding of an inhibitor with that of a natural peptide to Ca saturated calmodulin (holo-CaM). As inhibitor we have chosen trifluoperazine (TFP) that is inducing a huge conformational change of holo-CaM from the open dumbbell-shaped to the closed globular conformation upon binding. On the other hand， melittin is used as model peptide， which is a well-known natural binding partner of holo-CaM. The experiments are carried out as a function of pressure to reveal the contribution of volume or packing effects to the stability of the calmodulin-ligand complexes. From high-pressure Fourier transform infrared (FTIR) spectroscopy， we find that the holo-CaM/TFP complex has a much higher pressure stability than the holo-CaM/melittin complex. Although the analysis of the secondary structure of holo-CaM (without and with ligand) indicates no major changes up to several kbar， pressure-induced exposure of α-helices to water is most pronounced for holo-CaM without ligand， followed by holo-CaM/melittin and then holo-CaM/TFP. Moreover， structural pressure resistance of the holo-CaM/TFP complex in comparison with the holo-CaM/melittin complex is also clearly visible by higher Ca affinity. Förster resonance energy transfer (FRET) from the Tyr residues of holo-CaM to the Trp residue of melittin even suggests some partial dissociation of the complex under pressure which points to void volumes at the protein-ligand interface and to electrostatic binding. Thus， all results of this study show that the inhibitor TFP binds to holo-CaM with higher packing density than the peptide melittin enabling a favorable volume contribution to the inhibitor efficiency.