Equine herpesvirus 1 was established in adult mice by means of intranasal inoculation. A disease developed that showed several features closely resembling the infection in the natural host. These included the restriction of virus replication to the respiratory tract and blood, the replication of virus in ciliated mucosa, and development of viremia for several days during the acute phase of the infection. Infected mice were treated with the antiviral agent (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine. A marked effect was observed on virus replication in the respiratory tract when chemotherapy was commenced 1 day before virus inoculation; it also cleared the viremia and reversed the progression of clinical signs. When chemotherapy was commenced 1 day after virus inoculation, a moderate, though less marked effect was observed. The efficacy of this drug in the murine infection correlated with activity of the drug against equine herpesvirus 1 in cell cultures. The prospects for chemotherapy in the natural host are discussed in the light of these findings.