A strain of Sindbis virus (SV), recently isolated from mosquitoes in Israel, was used as a source for variants which differ in neuroinvasiveness and virulence that were generated by serial passage of SV in suckling and weanling mouse brain. At the 15th passage a neurovirulent variant was observed and designated SVN (neurovirulent). After 7 more passages in weanling mouse brains, another variant was observed and designated SVNI (neuroinvasive) and both were isolated and purified. All strains caused similar viremia after intraperitoneal (I.P.) injection of weanling mice, but whereas SV was neuroinvasive but nonvirulent, SVN was neurovirulent but noninvasive and SVNI was both virulent and invasive. SVNI is the first SV variant which is both neurovirulent and neuroinvasive in weanling mice. Co-injection I.P. of SV + SVN resulted in presence of SV alone in the mouse brain; co-injection of SVNI + SVN resulted in full-titered replication of both strains in the brain. We assume that this is achieved through a breach of the blood brain barrier effected by SVNI replication and used by SVN for co-invasion. SV probably invades the brain by a different mechanism. I.P. infection with SVNI of inbred BALB/c mice gave rise to clinical signs only in a few mice even though substantial viremia was demonstrated.