Mutants of mammalian reoviruses, enteric double-stranded-RNA-containing viruses that spread systemically after primary replication in intestinal tissue, have been extensively studied as models of viral pathogenesis. While reovirus serotype 3 strain Dearing (T3D) causes acute encephalitis in newborn mice, adult severe combined immunodeficient (SCID) mice develop chronic infection with T3D, with some mice living more than 100 days after infection (B. L. Haller, M. L. Barkon, G. P. Vogler, and H. W. Virgin IV, J. Virol. 69:357-364, 1995). To determine whether organ-specific reovirus variants are selected during chronic infection, we characterized the pathogenetic properties of two variants of T3D isolated 87 days after intraperitoneal infection of adult SCID mice. A brain-specific variant (T3DvBr) (i) grew to a higher titer than T3D in SCID mouse brain (but not intestine) after intraperitoneal inoculation, (ii) killed adult SCID mice faster than T3D, and (iii) grew well in neonatal NIH Swiss [NIH(s)] mouse brain tissue after intramuscular but not peroral inoculation. An intestine-specific variant (T3DvInt) (i) grew to a higher titer than T3D in SCID mouse intestine (but not brain) after intraperitoneal inoculation, (ii) killed SCID mice with kinetics equivalent to those of T3D, (iii) was much less virulent than T3D in neonatal NIH(s) mice, (iv) grew better than T3D in intestines after intramuscular or peroral inoculation into neonatal NIH(s) mice, and (v) grew poorly in brain tissue of neonatal NIH(s) mice after intramuscular inoculation. During prolonged infection of SCID mice, organ-specific variants of T3D, which are more efficient than wild-type T3D at one specific stage in reovirus pathogenesis, are selected.