The interaction of a polyoxometal (POM), K6SiW11Co(H2O)O39.10H2O (K6) as a Keggin, with human serum albumin (HSA) was studied by different methods and techniques. Binding studies show two sets of binding sites for interaction of POM to HSA. Binding analysis and isothermal calorimetery revealed that, the first set of binding site has lower number of bound ligand per mole of protein (ν), lower Hill constant (n), higher binding constant (K), more negative entropy (ΔS) and more electrostatic interaction in comparison to the second set of binding site. In addition, differential scanning calorimetery (DSC) and spectrophotometery data showed that, there are two energetic domains. The first domain is less stable (lower Tm and Cp) which corresponds to the tail segment of HSA and another with more stability is related to the head segment of HSA. Polyoxometal also decreases the stability of protein as Tm, secondary and tertiary structure as well as quenching of the fluorescence decrease. On other hand, perturbations in tertiary structure are more than secondary structure.