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Members of the Theiler's murine encephalomyelitis virus GDVII subgroup, which includes GDVII strain, are highly neurovirulent and induce a rapidly fatal polioencephalomyelitis. By contrast, Theiler's original subgroup members, which includes DA strain, are not as neurovirulent, and produce a chronic, demyelinating disease with virus persistence. We investigated the importance of the carboxyl region of the capsid protein VP1 in TMEV-induced disease since a trypsin-cleavable immunodominant neutralization epitope is situated in the VP1 carboxyl region, and since this region is believed to lie adjacent to the putative receptor binding site. The present studies support the role of DA VP1 residue 268 (and the aligned GDVII VP1 270) in Theiler's murine encephalomyelitis virus-induced CNS disease; however, the effect of this residue varies depending on its context: mutation of DA VP1 268 attenuates demyelination; mutation of GDVII VP1 270 in a GDVII/DA recombinant virus has no effect on demyelination but reduces early deaths (neurovirulence); mutation of GDVII VP1 270 in GDVII virus has no effect on neurovirulence. These data suggest that DA VP1 268/GDVII VP1 270 are not functionally equivalent and that a residue in recombinant viruses can differ in function from the same residue situated in a parental strain. Additional mutagenesis studies suggest that: the trypsin cleavage site of TMEV, which affects virus viability, is located at the lysine at DA VP1 261 (GDVII VP1 263); GDVII VP1 276, the predicted carboxyl terminus of VP1, affects VP1/2A processing and virus infectivity.