Susceptibility to Mycobacterium paratuberculosis, strain ATCC 19698, infection was compared histologically and morphometrically between 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 days after inoculation. In contrast, both the granulomatous lesions and number of bacteria decreased drastically in C3H.HeJ mice beginning at 6 weeks post inoculation. There were histological differences in granulomatous lesions between BALB/c and C3H/HeJ mice, indicating that the two strains differ in the 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 disseminated widely, especially in BALB/c mice. Our results suggest that the innate susceptible BALB/c mice and the innate resistant C3H/HeJ mice may be a useful and convenient model for further studies of immunoregulation and antimicrobial therapy of paratuberculosis.