We study the effect of the solvent (water) on the ligand exchange reaction (LER) step of Pt(II) complexation to PAMAM dendrimers. The results suggest that aquation of tetrachloroplatinate anion (PtCl42-) inside PAMAM outer pockets occurs prior to its reaction with dendrimer atom binding sites. Thus, the active involvement of water opens up several pathways by which Pt(II) can bind to tertiary amine sites (N3). Monodentate binding pathways by which a PtCl3- moiety is obtained as a final product rather than PtCl2(H2O) are considered to be the predominant routes due to their smaller degree of complexity, including aspects such as less number of intermediates and lower energy barriers. Monodentate binding of Pt(II) to the secondary amide site (N2) is found to be feasible, in agreement with previous NMR experiments, once aquation of the tetrachloroplatinate anion has occurred. For this type of binding to occur, the dendrimer branch amide group configuration would have to switch from its equilibrium position (trans) to a cis position. It is also found that outer pockets aid Pt(II) complexation with the dendrimer mainly by making the noncovalent binding (NCB) step more favorable than that in branchless environments. Finally, our results predict that competitive monodentate binding of Pt(II) to either N3 or N2 is thermodynamically rather than kinetically driven. © 2008 American Chemical Society.