2('),3(')-Didehydro-2('),3(')-dideoxynucleosides are clinically relevant antiviral agents. These nucleosides could be degraded under acidic conditions. Acidic stability studies showed the D4N had the following increasing stability order: D4G<cyclo-D4G#10877;RVT<D4T with half-lives ranging from less than 2 min to 35 days. A concerted A-1 mechanism has been proposed for the acidic cleavage of D4-nucleosides. The cleavage products were characterized as furfuryl alcohol and the corresponding nucleobase. Furfuryl alcohol is an agent found in many everyday food products. The biological results demonstrated that furfuryl alcohol had neither anti-HIV activity nor cytotoxicity in vitro, suggesting the acid instability of D4-nucleosides is unlikely to have an impact on the toxicity of these nucleoside analogs in humans.