OBJECTIVE To evaluate cell-mediated and humoral immune responses of calves receiving 2 doses of a dual-adjuvanted vaccine containing inactivated bovine herpesvirus type 1 (BHV1) and bovine viral diarrhea virus types 1 (BVDV1) and 2 (BVDV2) before and after exposure to BHV1. ANIMALS 24 Holstein steers negative for anti-BHV1 antibodies and proliferative cell-mediated immune responses against BHV1 and BVDV. PROCEDURES Calves were randomly assigned to 3 groups. The vaccinated group (n = 10) received 2 doses of vaccine on days 0 and 21. Control (n = 10) and seeder (4) groups remained unvaccinated. Calves were commingled during the study except for the 3-day period (days 53 to 55) when seeders were inoculated with BHV1 (1.04 × 107 TCID50, IV) to serve as a source of virus for challenge (days 56 through 84). Rectal temperature and clinical illness scores were monitored, and blood and nasal specimens were obtained for determination of clinicopathologic and immunologic variables. RESULTS After BHV1 challenge, mean rectal temperature and clinical illness scores were lower for vaccinates than controls. In vaccinates, antibody titers against BHV1 and BVDV2, but not BVDV1, increased after challenge as did extracellular and intracellular interferon-γ expression, indicating a T helper 1 memory response. Additional results of cell marker expression were variable, with no significant increase or decrease associated with treatment. CONCLUSIONS AND CLINICAL RELEVANCE Calves administered 2 doses of a killed-virus vaccine developed cell-mediated and humoral immune responses to BHV1 and BVDV, which were protective against disease when those calves were subsequently exposed to BHV1.