The comparative pathology of Herpesvirus papio 2 (HVP2) of baboons and SA8 virus of African green monkeys relative to that of herpes simplex virus (HSV1) of man was investigated in young adult mice inoculated intramuscularly and observed for 21 days. The 50% infectious dose (ID(50)) for HVP2 was approximately 10(2.0) plaque-forming units (PFU), while the ID(50) for HSV1 and SA8 was 10(2.5) and 10(3.8), respectively. There were marked differences in the ability of these three viruses to invade the central nervous system (CNS) and cause clinical neurological disease. HSV1 produced neurological signs in a few animals given 10(6)PFU, but SA8 did not. In contrast, HVP2 readily invaded the CNS and produced fatal disease with doses as low as 10(2)PFU. Two isolates of HVP2 tested had a 50% CNS disease dose (CNSD(50)) of 10(2.5) and 10(3.0)PFU and an LD(50) of 10(3.8) and 10(4.3)PFU, respectively. Histopathological examination of tissue from HVP2-infected mice revealed severe lesions of inflammation and necrosis in the central, peripheral and autonomic nervous systems, as well as of other tissues including skin, adrenal glands and the gastrointestinal tract. Viral antigens were detected immunohistochemically in lesions. This study showed that while both HVP2 and SA8 could infect mice, there were marked differences in the ability of these two closely related viruses to cause clinical disease and CNS lesions. This murine model may prove useful in the investigation of viral or host determinants responsible for the varying neurovirulence of these simian alpha-herpesviruses.