In addition to the human immunodeficiency virus (HIV), virtually all adults with the acquired immunodeficiency syndrome (AIDS) have been infected with one or more herpesviruses, which contribute to morbidity, mortality, and may enhance HIV replication. Given the need for an agent capable of controlling the replication of both HIV and herpesviruses, we report here the synthesis and broad-spectrum antiviral activity of two oxetanocin analogues, (±)-9-[(1R,2α,3β)-2,3-bis(hydroxymethyl)-1-cyclobutyl]adenine ((±)-cyclobut-A) and (±)-9-[(1R,2α,3β)-2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine ((±)-cyclobut-G). In vitro assays showed these compounds had potent activity against herpesviruses including HSV-1, HSV-2, CMV, VZV, and EBV, with low ED50 and high ID50 values indicating good selectivity, and they protected ATH8 cells from HIV-1. In vivo studies in mice demonstrated cyclobut-A and cyclobut-G effectively treated HSV-2 encephalitis and systemic HSV-1 infection, with cyclobut-A showing superior efficacy to ara-A. These compounds are promising broad-spectrum antivirals with potential utility for AIDS therapy.