Caseous lymphadenitis (CIA) caused by Corynebacterium pseudotuberculosis is a worldwide disease of sheep and goats and is characterized by development of pyogranulomas in lymph nodes and lungs. Control of this disease by vaccination remains controversial, although toxoid vaccines are now commercially available in some countries. To determine the efficacy of acquired immunity to control CLA, the effect of primary infection on subsequent challenge exposure was investigated. Adult seronegative ewes were primarily inoculated with a streptomycin-sensitive strain of C pseudotuberculosis on the external part of the left ear and thereafter challenge-exposed by inoculation of the streptomycin-resistant strain 19R in the right ear. This protocol indicated that primary infection with at least 10(7) viable bacteria induced strong protection against subsequent challenge exposure; the ewes with primary infection did not develop lesions as a result of challenge exposure, whereas immune-naive ewes developed numerous pyogranulomas in the right car, in lymph nodes draining the inoculation site, and in the lungs. However, ewes with primary infection remained carriers of the disease as a result of primary inoculation. These results offer experimental support for development of more effective vaccination to control CLA, in sheep and goats, and this model indicates that animals with primary infection can be used as positive controls for protection when testing a candidate vaccine against CLA.