The stereoselective stability of oligodeoxyribonucleotide methylphosphonates is examined using free-energy computer simulations. These modified phosphate linkages have the potential to be important antisense therapeutics that can be targeted on specific sequences of single- and double-stranded DNA, as well as crucial RNA messages. The stability of hybrid duplexes that contain these modified linkages is known experimentally to depend on the configuration of the chiral phosphonate center. Free-energy decomposition calculations were performed on three DNA oligomers to determine the origin of the structural interactions and physical properties that influence the relative stability of R and S methylphosphonate diastereomers. The strategy applied used free-energy decomposition methods to evaluate the free-energy contributions from selected groups. The results indicated that only three groups have a steric effect on the stability: the C2' and C3' substituents on the S diastereomer (5' side) and the C5' substituents on the R diastereomer (3' side). The balance considerably favors the R configuration in all the isomers studied and is not sequence dependent. The electrostatic effects were much more variable and were shown to be dependent on the conformation of duplex. The solvent interactions, however, were consistent and contributed favorably to the stability of the R over the S diastereomer. This favorable solvation energy for the R diastereomer was surprising (since the methyl group is more solvent exposed in this configuration) and was further supported by ab initio and associated free-energy calculations. This study concludes that oligonucleotides containing R-methylphosphonate linkages will normally form more stable duplexes than the corresponding S diastereomer irrespective of sequence, but also points that conformational changes may allow for a reversal in stability.