Tyzzer's disease was induced experimentally in nonimmunosuppressed, weanling Mystromys albicaudatus by oral inoculation with Bacillus piliformis spores. Focal areas of necrosis bordered by cells containing B. piliformis were observed first in the tunica muscularis of the intestine and in the periportal region of the liver 3 days post-inoculation, in the ventricular myocardium 7 days post-inoculation and in the brainstem 9 days post-inoculation. Healing in the tunica muscularis, liver and myocardium was accompanied by granuloma formation. The findings indicate that Mystromys are susceptible to B. piliformis infection. This is, to our knowledge, the first time brain lesions have been reported in any species following oral inoculation with B. piliformis. Tyzzer's disease should be considered as a possible diagnosis in Mystromys with hepatoenteritis, myocarditis, or indications of central nervous system disorders.