Viral infections of the central nervous system (CNS) following peripheral inoculation of Sindbis viruses were studied. The use of viral strains, which vary in their neuroinvasive and neurovirulent properties, and various strains of mice, which differ in immunocompetence, revealed several pathways of viral neuroinvasion in adult mice. A genetic-trait dependent mechanism was exhibited by the neuroinvasive viruses, showing a similar pattern in all mice strains tested. A second mechanism, dependent on a prolonged high viral load, was exhibited by a noninvasive variant in Severe Combined ImmunoDeficient (SCID) mice. The absence of antiviral antibodies in SCID mice allowed the maintenance of a long-term high viremia, leading to a random entry to the CNS and proliferation in brain tissue. An additional pathway for neuroinvasion was induced upon disruption of the blood-brain barrier activity by exogenous reagents and was demonstrated in cases of short lived high viremia of noninvasive viruses.