In this study transgenic mice which expressed antisense RNA against the nucleocapsid protein gene of mouse hepatitis virus (MHV) under the control of RSV LTR were produced. These transgenic mice were able to transmit the foreign gene to their progeny in a Mendelian fashion. Antisense RNA was detected in various tissues from the transgenic mice including liver and brain, the target organs of MHV infection. One strain of transgenic mice derived from founder mouse No. 19 was more resistant to the lethal challenge of MHV than non-transgenic mice. The results of the present study show the ability of antisense RNA against the viral gene to protect against viral infection in vivo.