Summary The effects of the synthetic polyanionic interferon inducers maleic acid/divinyl ether copolymer (MA/DVE) and polyinosinic/polycytidylic acid (polyrI/polyrC) were studied in mice challenged intranasally with vesicular stomatitis virus. Young (14-day or 24-day) animals were used. Either local (intranasal) or systemic (intraperitoneal) treatment protected significantly against virus infection. Optimal local protection was given by 40 µg. of polyrI/polyrC instilled 4 hr before virus challenge. Intraperitoneal MA/DVE exerted a more durable effect lasting for at least 10 days, and polyrI/polyrC proved to be active when applied several days after inoculation of virus. PolyrI/polyrC treatment started after virus in the brain had reached maximum concentration retarded progression of the disease, but when delayed until clinical signs of illness occurred, polyrI/polyrC treatment was not effective. The protective activity of MA/DVE and polyrI/polyrC injected intraperitoneally against virus infection at a distant site suggested the mediation by a systemic antivirus state, presumably due to interferon production.