The interaction between human serum albumin (HSA) and two porphyrin-based tetra-cationic photosensitizers were investigated via spectroscopic techniques (steady-state, time-resolved fluorescence and circular dichroism) combined to theoretical calculations (molecular docking). Similarities and differences in the binding behavior of a porphyrin bearing peripheral chloro(2,2′bipyridine)platinum(II) complexes (4-PtTPyP) versus methyl groups (4-MeTPyP) attached in the N-pyridyl atoms were evaluated. There is a ground state association between HSA-porphyrins (static fluorescence quenching mechanism), with Ka values for 4-PtTPyP slightly higher than 4-MeTPyP. While the binding 4-MeTPyP is primarily enthalpically driven, 4-PtTPyP binds mainly due to hydrophobic forces in an entropically driven association. Far-UV CD showed that 4-PtTPyP perturbs the thermal stability of the protein, probably due to high volume of the porphyrin. Molecular docking suggested that 4-PtTPyP stablish a larger number of interactions with the neighboring amino acid residues. The likely location for the binding pocket is in subdomain IB, located in an external region of the protein structure. The bulky peripheral platinum(II)-complexes does not have a deleterious effect upon serum albumin binding spontaneity and extension, although modifies the nature of the complex formed.