Respiratory disease is one of the most important diseases in sheep and cattle and economic losses due to disease are so important for food animal producing country. Tulathromycin (TUL) is a semi-synthetic, long acting Antibiotic which belongs to the macrolide group. It uses as an antibiotic in the treatment of respiratory diseases in domestic animals. In this study 200 calves that exhibiting clinical signs of respiratory disease with undifferentiated etiology selected & divided in to two groups. Group 1 treated with single injection of TUL 2.5 mg/kg BW SC and Group 2 treated with combination of oxytetracycline(OTC) 20 mg/kg BW IM & florfenicole (FFC) 40 mg/kg BW SC. Treated animals were examined 5 days after injection. In the first group (TUL) 89 calves showed sings of cure 5 days later after first injection. 11 calve needed further treatment in which 5 calve cured and 6 calve died. In the second group (OTC & FFC) 84 calves showed sings of cure 5 days later after single injection. 16 calves needed further treatment, of which 7 calves cured and 9 calves died. The results of this study indicates that usage of TUL is more effective than combination of FFC & OTC in treatment of respiratory disease with undifferentiated etiology and efficacy increased & mortality rate decreased considerably.