The objectives of this study were to determine the efficacy of intramuscular administration of ceftiofur to reduce the incidence of case-related death and culling following severe clinical mastitis in lactating dairy cattle. A total of 104 cows with severe clinical mastitis (systemic signs) were enrolled in the study and randomly assigned to one of two treatment groups. Immediately after detection of the case, one group was administered 2.2 mg/kg of ceftiofur intramuscularly, and the dose repeated at 24-h intervals for a total of five doses. The second group of cows did not receive systemic antibacterial therapy. Additionally, all cows in both treatment groups received intramammary pirlimycin (Pirsue®) in the affected quarter every 24h for a total of up to three doses. Also at the onset of the case, all cows on the trial were administered a supportive therapeutic regimen of fluids and anti-inflammatory agents that varied from farm to farm, but was standard within each herd at the discretion of the herd manager and veterinarian. Of all cases 14/104 (13.5%) resulted in a lost cow (died or culled). The proportion of cases that resulted in a lost cow and were treated with ceftiofur (4/51; 7.8%) did not statistically differ from cows that were not treated with ceftiofur (10/53; 18.9%). However, the proportion of cases that resulted in lost cows was higher for those cases that yielded a coliform organism on culture (14/56; 25.0%) than cases that did not yield coliforms (0/48; 0.0%; P<0.001). Thus, among coliform cases, cows that were not treated with ceftiofur were more likely to be culled or die (10/27, 37.0%; P<0.05) than cows treated with ceftiofur (4/29, 13.8%). We conclude that intramuscular administration of ceftiofur did not affect the outcome of severe clinical mastitis when all etiologic agents are included in the analysis. However, for severe clinical mastitis cases caused by coliform organisms, ceftiofur therapy reduced the proportion of cases that resulted in cow death or culling. This benefit may be realized because of the amelioration of bacteremic-related pathogenesis.