Gossypol, a disequiterpene obtained from cottonseed oil, and a series of peri-acylated gossylic nitriles were compared for their antiviral activities against HSV-II and for their toxicities to the host Vero cells. All of the peri-acylated gossylic nitriles exhibited lower cytotoxicities to the host cell than did the parent compound gossypol. Both gossypol and the series of derivatives exhibited antiviral activities against HSV-II when the virus was treated with drug at concentrations as low as 5 X 10(-7) M. Two of the derivatives, gossylic nitrile-1,1'-diacetate and gossylic nitrile-1,1'-divalerate, were capable of inhibiting viral multiplication in Vero cells that were infected with virus before administration of the drug. The results of this study indicate that modification of the aldehyde functional groups on gossypol lowers the toxicity of this drug but does not abolish its antiviral properties. Derivatives of gossypol may be useful antiviral agents.