Two series of optically pure 2,4-disubstituted 1,3-dioxolanes and -1,3-oxathiolane nucleosides containing (E)-5-(2-bromovinyl)uracil were synthesized and assayed for activity against HSV-1, HSV-2 and HCMV replication in vitro. The β-L (2S,4S) dioxolane nucleoside 10 displayed significant activity against HSV-1, whereas the β-D (2R,4R) oxathiolane 14 demonstrated potent activity against HSV-2. The α-L (2S,4R) dioxolane 11 and oxathiolane 17 were moderately active against HSV-1 and HSV-2, respectively.