Two convergent approaches for synthesizing a new class of nucleoside diphosphate prodrugs bearing different nucleoside analogs are reported herein. The DiPPro-nucleotides comprise an acyloxybenzyl group in combination with a lipophilic alkyl residue at the β-phosphate or β-phosphonate group, respectively. They are selectively cleaved to form their corresponding β-alkylated nucleoside diphosphate derivatives in chemical and biological hydrolysis studies. In contrast, there is a selective but slow cleavage observed in the hydrolysis of the DiPPro-compounds bearing two different, nonbioreversible alkyl moieties in human CD4+ T-lymphocyte CEM/0 cell extracts. In these studies, the delivery of nucleoside monophosphates rather than nucleoside diphosphates is being observed, most likely due to a pure chemical phosphoranhydride cleavage of the β-phosph(on)ate moiety. The antiviral evaluation of these two types of prodrugs reveals that these compounds exhibit marked anti-HIV efficacy in HIV-2-infected thymidine kinase-deficient CD4+ CEM T-cells (CEM/TK−), with significantly better activities (up to 6700-fold) against HIV-2 replication than the parent nucleosides. Primer extension assays demonstrate that the β-dialkylphosphate-modified nucleoside derivatives, β-monoalkylated-diphosphates, and nucleoside diphosphates serve as substrates for HIV reverse transcriptase for the viral DNA elongation.