Infection of the peripheral nervous system was studied after inoculation of HSV into the flank skin of H-2 congenic mice. The amount of virus recovered from the sensory ganglia varied significantly between the mouse strains tested. Differences became apparent 7 d after infection, at which time the severity of disease in H-2k mice was two to three orders of magnitude greater than that in H-2d animals. The association of the H-2k haplotype with impaired ability to clear HSV from the nervous system is the first clear demonstration that genes within the MHC can influence the severity of primary herpetic infection, in spite of numerous studies on genetic resistance to this disease.