Severe combined immunodeficient/beige (Scid/bg) mice were infected intraperitoneally (IP) with a single injection of 1 x 10⁵M. paratuberculosis (MPTB) organisms. There was histologic evidence of infection within one month of inoculation. The earliest lesions consisted mainly of foci of mononuclear cells with and without acid-fast bacteria. These lesions which gradually enlarged and coalesced developed in a time-dependent fashion, appearing first in the liver, then the spleen and finally in the intestines. No lesions/acid-fast organisms were ever seen in the heart, kidney and lungs of test or control mice. By 12 weeks post-infection, mice developed significant weight loss compared to their uninfected controls, and by 22 weeks becmae emaciated, mimicking clinical paratuberculosis in ruminants. Tubour necrosis factor-alpha was not detectable in the plasma of infected mice as determined by a double sandwich ELISA. Our results show that Scid/bg mice can be easily and consistently infected I.P. (58 out of 58) with relatively few MPTB organisms and consistently develop cachexia. We propose the Scid/bg mouse as a useful model for the study of immunopathogenesis, cachexia and therapy in MPTB infections.