Efficacy and field safety of tulathromycin administered as a single-dose treatment to crossbreed beef calves with undifferentiated bovine respiratory disease (BRD) were evaluated in a multicenter field study conducted at four US feedlots. Two hundred castrated male calves were enrolled at each study site. The treatment groups were physiologic saline (n = 160) given SC at 0.02 ml/kg, tulathromycin (n = 320) given SC at 2.5 mg/kg, and tilmicosin (n = 320) given SC at 10 mg/kg. Nasopharyngeal swabs for bacterial culture were obtained before treatment. The cure rate for calves treated with tulathromycin (78%) and tilmicosin (65%) was significantly (P < or = .0001) higher than that of calves treated with saline (23.8%). The cure rate of calves treated with tulathromycin (78.4%) was significantly (P = .0007) higher than that of calves treated with tilmicosin (64.9%). No adverse events related to tulathromycin were reported. Under the conditions of this study, tulathromycin administered as a single-dose treatment was efficacious in the treatment of undifferentiated BRD.