Low-generation viologen-phosphorous dendrimers (VPDs) can be exploited as novel therapeutic agents, since they efficiently inhibit aggregation of amyloid-beta into fibrils and are active against several strains of microorganisms. Human serum albumin (HSA), the most abundant plasma protein, is playing an increasing role as drug carrier in the clinical setting. Therefore, with the aim of exploiting HSA as a potential carrier for VPDs, in this work we performed a preliminary investigation of the interaction of six different VPDs 1-6 with HSA using a combined computational/experimental approach. First, different modeling techniques were employed to i) determine the dendrimer binding site on the HSA surface; ii) derive the free energy change Delta G(b) involved in each dendrimer/HSA complex formation; iii) analyze in details all molecular determinants contributing to Delta G(b), and iv) evaluate the eventual HSA structural variations induced by dendrimer binding. All modeling predictions were next validated using a series of experimental techniques, including isothermal titration calorimetry (ITC), circular dichroism (CD), and fluorescence quenching and decay. In aggregate, the results from this study allowed us to rank the affinity of the different viologen-phosphorous dendrimers 1-6 towards HSA and to formulate a molecular based rationale for the differential binding thermodynamics of the resulting dendrimer/HSA complexes. According to our data, HSA can successfully and selectively bind VPDs 1-6, dendrimer 4 being the best cargo for this endogenous protein nanocarrier. (C) 2016 Elsevier B.V. All rights reserved.