Various 2,3'-anhydro analogs of 5-substituted 1-(2-deoxy-β-d-lyxofuranosyl)uracils (10-15) and a related 1-(3-O-mesyl-2-deoxy-β-d-lyxofuranosyl) pyrimidine nucleoside analog (18) have been synthesized for evaluation as a new class of potential anti-HBV agents. The compounds 10, 12, and 15 demonstrated most potent anti-HBV activities against duck HBV (DHBV) and human HBV with EC(50) values in the range of 2.5-10 and 5-10 μg/mL, respectively, at non-toxic concentrations (CC(50) = > 200 μg/mL). The nucleoside 18 also demonstrated significant anti-HBV activity against DHBV with an EC(50) value of 2.5 μg/mL, however, it was less active against HBV in 2.2.15 cells (EC(50) = > 10 μg/mL).