We formulate a model that determines the net benefit of Johne’s disease vaccination within a tuberculosis-accredited region given the extra costs associated with the vaccine-related cross-reactivity with tuberculosis test results and the probability of a tuberculosis outbreak. We apply the model to Minnesota and Michigan, where tuberculosis has recently become endemic. The expected benefit of Johne’s vaccination of $53.03 per cow exceeds the cost of Johne’s cross-reactivity of $32.72 and $32.42 per cow within each of the two Minnesota tuberculosis regions, as well as $31.99 and $30.78 per cow within each of the two Michigan tuberculosis regions.