We report on the synthesis and evaluation of three different nucleotide prodrug systems: (i) nucleoside triphosphate analogues in which the γ-phosph(on)ate has two different lipophilic nonbioreversible alkyl residues with d4TDP as the released nucleotide analogue; (ii) nucleoside diphosphate analogues bearing a bioreversible and a stable β-alkyl group; or (iii) nucleoside diphosphate analogues bearing two nonhydrolysable lipophilic alkyl moieties. The delivery of d4TDP (for the triphosphate precursor) and d4TMP (for the diphosphate precursor) was demonstrated in CD4+ T-lymphocyte CEM cell extracts as well as in phosphate buffer saline (PBS). In primer extension assay, we found that γ-dialkylated d4TTP derivatives and d4TDP were accepted as substrates by HIV-RT. Several of these compounds were observed to be extremely active against HIV-1/2 replication in HIV-infected cells. A more than 45,000-fold increase in the anti-HIV activity was detected for compound 18a as compared to the parent d4T which results in a selectivity index value of 37,000.