BACKGROUND A randomized, masked, 2-arm parallel trial was conducted to assess the efficacy of a Moraxella bovis (M. bovis) autogenous vaccine to prevent naturally occurring infectious bovine keratoconjunctivis (IBK) in beef calves. OBJECTIVE The null hypothesis was that treatment group was not associated with either risk of IBK or last observed weight. METHODS The trial was conducted between May and November 2009 and 2010 on a university-owned farm in Iowa. The vaccine contained 2 randomly selected M. bovis from IBK cases that occurred at the farm in 2008. Calves born between January and May 2009 and 2010 without visible corneal lesions were randomly allocated to receive vaccine (n = 191) or placebo (n = 178). METHODS Two s.c. doses were administered 21-28 days apart. Allocation to treatment was concealed using bottles marked A or B. Staff observing the animals for IBK could not determine the treatment grouping. The herd met the "at-risk" criteria (ie, >15% IBK in unvaccinated calves and M. bovis detection in IBK cases). Analysis was "per-protocol". RESULTS The risk of IBK was 58/185 (31%) in vaccinated calves and 66/173 (38%) in unvaccinated calves (adjusted risk ratio = 0.78; 95% CI, 0.49-1.24). Average weight before sale did not differ between the vaccinated calves (196.6 kg, SD ± 39.9) and unvaccinated calves (198.1 kg, SD ± 42.7) (P value = .19). No adverse effects were noted. CONCLUSIONS Combination of the study results with previous studies suggests that autogenous M. bovis vaccines often are ineffective in controlling naturally occurring IBK.