On the hypothesis that one carbon homologation of 4'-selenonucleosides might relieve the steric repulsion between cellular kinases and bulky selenium, 5'-homo-4'-Se-d4Ns, 3a-e,a sa nti-HIV agents were designed and synthesized stereoselectively from d-gulonic g-lactone, with the conversion of 2',3'-diol into the olefin as the key step. The anti-HIV activity of all synthesized compounds, 5'-homo-4'-Se-d4Ns, was toxicity-dependent, unlike normal4 '-Se-d4Ns, which were inactive against HIV-1. This result indicates that 5'-homo-4'-Se-d4Ns might be phosphorylated by cellulark inasesa sp er the hypothesis.