The interaction between proteins and a radiological commonly-used contrast medium (iopamidol) have been studied by calorimetry. When aqueous solutions of fibrinogen or of lysozyme (20 g/l) are mixed with an aqueous solution of iopamidol (1,3-5 benzendicardoxamid,N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5- [(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo) in the clinical blood concentration range (26-485 mM), isothermal calorimetry reveals a weak endothermal interaction at a high concentration of iopamidol for both proteins. This endothermal effect does not appear to be due to direct protein-iopamidol association. Differential scanning calorimetry confirms the influence of iopamidol by the change in protein unfolding in the presence of contrast medium, and suggests alterations in the protein solvation as a mechanism. Dilution studies indicate that iopamidol can influence protein solvation even when water molecules are present in a molecular excess of 1000. The influence of iopamidol on the availability of water molecules and the absence of direct interaction with the protein molecules is shown by Raman spectroscopy of two amino acids in the presence of iopamidol. The spectrum of alanine is unchanged at any iopamidol concentration studied, whereas the spectrum lines due to the thiol group of cysteine are shifted in a manner consistent with altered solvation.