Intracerebral infection of adult immunocompetent mice with most strains of lymphocytic choriomeningitis virus (LCMV) caused a systemic infection and led to severe meningoencephalitis and death due to the induced T cell immune response. The susceptibility of congenic mice to the two plaque variants Docile and Aggressive of LCMV strain UBC was shown to be mouse strain-dependent. To investigate the possible correlation between acid-stable interferon (IFN) and natural killer (NK) cell responses and the susceptibility to the two UBC LCMV substrains, serum titres of acid-stable antiviral activity, presumably IFN-alpha, beta and NK cell activities were determined in various mouse strains at different times after intracerebral infection. The two viral isolates induced comparable IFN-alpha, beta serum titres and caused similar NK activities in the same mouse strain. Between different mouse strains, marked differences in the kinetics and amount of IFN production were observed, yet there was no correlation with the susceptibility to the two UBC LCMV substrains. Additionally, there was no correlation between the magnitude of the IFN-alpha, beta serum titres and the NK activities induced in the spleen by the viral inocula. Overall, the findings suggest that levels of circulating IFN-alpha, beta are only of minor importance for the development of LCM disease.