Treatment of BALB/c mice with poly(A):poly(U) 18 h prior to infection with a lethal dose of murine cytomegalovirus (MCMV) increased survival. In parallel with increased survival, a 10- to 100-fold reduction of plaque-forming MCMV was found in the liver and spleen of mice 4 days post-infection with a sublethal dose of MCMV. Poly(A):poly(U) did not significantly increase natural killer cell activity or prolong the duration of elevated cytotoxic activity in infected animals. The possible role of interferon in the poly(A):poly(U)-induced protection of BALB/c mice is discussed.