It has been confirmed and further documented that infection of the rabbit cornea with the E-43 strain of HSV-1 precludes superinfection of the corresponding trigeminal ganglia by another HSV strain, i.e., the challenging virus does not establish latency and can not be recovered from the ganglia. It was shown that after primary infection, a state of resistance is established in the neuronal cells of the ganglia, and although the challenging strain reaches the ganglia, it does not cause discernible acute infection, and does not displace the resident virus in the ganglia. This protection was present 6 months after primary infection, was independent of immune factors such as circulating or secretory antibodies, and was localized to the point of entry of the primary infecting strain and the sensory neurons that innervate that site. The smallest inoculum that provided protection from ganglionic superinfection was that which produced overt disease in the eye, although different degrees of disease resulted from varying inocula above this minimum. Asymptomatic primary infections produced by subminimal inocula of the E-43 strain or by the HSV recombinant strain, F(MP)F, which is avirulent for the rabbit eye, protected against severe disease and death, but the degree of protection against ganglionic superinfection was variable and depended on the time of challenge. These findings suggest that susceptible neurons in the trigeminal ganglion, when "occupied" by an infecting strain, cannot be superinfected by a second strain.