Varicella-zoster virus (VZV) is responsible for primary infections as well as reactivations after latency inVaricella-zoster virus (VZV) is an alphaherpesvirus that is known to be responsible for varicella in young children and for localized recurrent lesions (called zoster) later in life, due to reactivation in the ganglia. The disease can be severe in immunocompromised patients such as AIDS patients or transplant recipients. The reference drug for the treatment of immunocompromised patients presenting with VZV infections and of patients presenting with zoster is acyclovir (ACV) (7). Recently, brivudine (BVDU), another nucleoside analog, has been marketed for the treatment of varicella and zoster (15,23).We have demonstrated that several members of a new class of antivirals, the bicyclic pyrimidine nucleoside analogues (BCNAs), are highly potent and selective inhibitors of VZV in vitro (3-5, 12, 13, 16-18). This new class of compounds exhibits exclusive specificity for VZV and obligatorily requires an alkyl or alkylaryl side chain at the furan moiety for potent anti-VZV activity.ACV-resistant VZV strains have been reported to emerge with increasing frequency in immunocompromised patients after long-term therapy with ACV (1). These observations justify drug sensitivity evaluation of resistant viral strains obtained after exposure to molecules belonging to different classes of antiviral agents.The present work demonstrates the exquisite antiviral activity of a selection of the most potent BCNAs against a broad range of clinical VZV isolates. These BCNA molecules were also investigated for their activity against VZV strains that were selected in the presence of several of the BCNAs, demonstrating that the BCNAs select for drug-resistant VZV phenotypes resulting from mutations in the virus-encoded thymidine kinase (TK).