Topical application of a mixture of acetylsalicylic acid (ASA) and diethyl ether is effective in the treatment of acute herpes zoster and postherpetic neuralgia. To study whether the other-than-analgesic effects of that treatment could be due to an antiviral activity of ASA the effects of the drug on the replication of varicella zoster virus (VZV) were assessed by the fluorescent focus assay on MRC5 and Vero cells. ASA caused a marked reduction in the spread of infection in MRC5 monolayers while in growing Vero cells the effective dose proved toxic. ASA concentrations (5-10 mM) which were effective in vitro against VZV are higher than the plasma concentrations attained in the standard treatment of chronic inflammatory states, but are consistent with the skin concentration attained by topical application of ASA/diethyl ether mixture. These data support similar findings relating the antiviral activity of acetylsalicylic acid to influenza virus, CMV, and HIV.