NMR spectroscopy has been used to observe the effects of the amine ligand on the rate of reaction of platinum diamine and triamine complexes with DNA and protein residues. Whereas [Pt(dien)Cl]Cl and [Pt(dien)(D2O)]2+ have been known to react faster with thioether residues such as N-AcMet than with 5′-GMP, we found that [Pt(Me4en)(D2O)2]2+ appeared to react faster with 5′-GMP. To quantitatively assess the factors influencing the rates of reaction, rate constants at pH 4 were determined for the reactions of [Pt(en)(D2O)2]2+ [en = ethylenediamine] and [Pt(Me4en)(D2O)2]2+ with N-AcMet, N-AcHis, 5′-GMP, and Guo (guanosine). In each case the less bulky complex ([Pt(en)(D2O)2]2+) reacts more quickly than does the bulkier [Pt(Me4en)(D2O)2]2+, as expected. Both complexes reacted faster with 5′-GMP; however, analysis of the rate constants suggests that the [Pt(en)(D2O)2]2+ complex favors reaction with 5′-GMP due to hydrogen bonding with the 5′-phosphate, whereas [Pt(Me4en)(D2O)2]2+ disfavors reaction with N-AcMet due to steric clashes. Bulk had relatively little effect on the rate constant with N-AcHis, suggesting that peptides or proteins that coordinate via His residues would not have their reactivity affected by bulky diamine ligands.