Phosphorothioate oligodeoxynucleotides (PS-oligo) complementary to a leader RNA of mouse hepatitis virus (MHV) were more effective inhibitors of MHV multiplication than natural oligodeoxynucleotides (PO-oligo). Sequence-dependent inhibition of viral multiplication was shown at low concentrations (0.001-0.1 microM) of antisense PS-oligo. Phosphorothioate oligodeoxycytidine, PS-(dC)20 and PS-oligo, which has no significant homology to the MHV sequence, showed inhibitory effects on MHV multiplication at concentrations higher than 0.5 microM. These results showed that PS-oligo was more potent than PO-oligo in inhibition of MHV multiplication and that PS-oligo may inhibit MHV multiplication by two different mechanisms, that is, in sequence-dependent and -independent manners.