A total of 894 calves at high risk for bovine respiratory disease were processed at two sites and randomly assigned to receive one of three antimicrobial metaphylactic regimens to determine if a two-drug regimen offered any advantage over the more conventional one-course regimens. On arrival, calves received either a two-course regimen of ceftiofur crystalline free acid (CCFA) followed by tulathromycin 8 days later (Group 1) or a one-course regiment of CCFA (Group 2) or tilmicosin (Group 3). At Site A, morbidity was significantly lower (52%) in Group 1 than in Group 2 (76.3%) and Group 3 (78.4%). At Site B, morbidity was significantly lower in Group 1 (2.6%) than in Group 2 (9.4%) and Group 3 (7.2%).