Susceptibility to Mycobacterium paratuberculosis strain ATCC 19698 infection was compared histologically and morphometrically in BALB/c (Bcgs) and C3H/HeJ (Bcgr) mice. The granulomatous lesions, containing M. paratuberculosis, in the liver and spleen of BALB/c mice increased progressively until 32 weeks after intraperitoneal inoculation. In contrast, both the granulomatous lesions and number of bacteria decreased drastically in C3H/HeJ mice beginning at 6 weeks after inoculation. There were histological differences in granulomatous lesions between BALB/c and C3H/HeJ mice, indicating differing functional activity of cellular immunity. Intestinal lesions similar to those seen consistently in bovine paratuberculosis were observed first at 6 weeks after infection and later became disseminated widely, especially in BALB/c mice. Our results suggest that the innately susceptible BALB/c mice and the innately resistant C3H/HeJ mice may be useful and convenient models for further studies of immunoregulation and antimicrobial therapy of paratuberculosis.