Isomeric fluorinated cyclobutane nucleoside analogs (t)-2 and (t)-3 were prepared via multi-step syntheses. Compound 2 is a potent inhibitor of herpes viruses in cell culture assays, while the configurational isomer 3 is devoid of antiviral activity. Fluorine substitution on the furanose ring of nucleosides has led to the discovery of potent antiviral agents, such as 1-(2'-deoxy-2'-fluoro-lt-p-D-arabinofuranosyl)-5-iodocytosine (FLQC). Moreover, promising antiviral activity for a number of fluorinated carbocyclic nucleoside analogs has recently been reported. These results, along with our interest in cyclobutane nucleoside analogs, prompted us to study the antiviral effects of fluorine substitution on the cyclobutane ring of (+)-1, a potent inhibitor of herpes simplex virus type 1 (HSV-1) and HSV-2. In particular, we chose to investigate the chemical syntheses and antiviral effects of fluorinated analogs 2 and 3. Herein, we report our results which demonstrate a striking difference in potency for these configurational isomers against a wide range of herpes viruses.