Effects of cold or isolation stress on brain penetration by the neurovirulent noninvasive Sindbis virus strain (SVN) were studied in mice. SVN injected intracerebrally (i.c.) causes acute encephalitis and kills adult mice but is unable to invade the brain and kill when injected intraperitoneally (i.p.). Mice inoculated i.p. with SVN were exposed to cold stress or were singly housed. Both stress patterns induced SVN encephalitis and death in 42% (cold) and 37% (isolation) of the tested mice. No death was observed in the control injected mice. Brain virus levels were found to be more than 10(6) PFU in all dying mice. No virus was detected in the control group brains. The virus that was isolated from the brains of moribund mice demonstrated no changes in neuroinvasive and neurovirulent properties. We suggest a stress induced blood-brain-barrier opening with subsequent virus entrance as the mechanism of stress induced SVN encephalitis.