The RL1 gene of herpes simplex virus (HSV) encodes a polypeptide, ICP34.5 which is a specific virulence determinant. RL1 null mutants fail to replicate in both the PNS and CNS and are incapable of causing encephalitis. Additionally, RL1 null mutants have the capacity to replicate in actively dividing cells but fail to replicate in growth arrested or terminally differentiated cells. This selective replication phenotype has highlighted their use as both tumour killing agents and gene delivery vehicles particularly to the nervous system. Before their full potential can be assessed, however, it is necessary to determine the pathological and immune responses induced following direct intracerebral inoculation. Fourteen mice were injected in the left cerebral hemisphere with a high dose of the HSV-1, RL1 null mutant 1716. At regular time intervals up to 28 days, the mice were killed and the distribution of virus antigen, histopathological changes and immune responses in the CNS determined by H & E staining and immunohistochemistry. Control mice were injected with either wild type HSV-1 or buffer. At early times post-inoculation with 1716, there is a low grade meningoencephalitis with a limited inflammatory response. This is accompanied by virus antigen expression confined to the site of inoculation. By 28 days the CNS is histopathologically normal; virus antigen and immune responses are no longer detectable. These findings demonstrate that infection of the CNS by RL1 null mutants of HSV results in a finite, self-limiting response and highlights their potential for therapeutic use.