Several viruses, including mouse hepatitis virus strain JHM (MHV-JHM), enter the brain after intranasal inoculation and spread transneuronally to other parts of the central nervous system (CNS). Both the olfactory and trigeminal nerves innervate the nasal cavity and are potential portals of virus entry into the CNS. To evaluate the relative importance of each nerve for MHV infection, mice were infected under conditions that discriminated between trigeminal and olfactory nerve entry. When olfactory nerve entry was selectively eliminated by surgical removal of both olfactory bulbs or by chemical destruction of the olfactory epithelium, MHV-JHM spread into the CNS was completely prevented. On the other hand, direct inoculation into the olfactory bulb, which eliminates all entry via the trigeminal nerve, had no effect on the pattern of virus infection. Thus MHV-JHM enters the CNS via the olfactory nerve after intranasal inoculation while entry via the trigeminal nerve is an insignificant part of this process.