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Leukodema like chronic skin disease in buffaloes refractive to usual treatment is encountered in Marathwada region of India. The disease is causing heavy economic losses to animal owners due to substantial reduction in market value. Hence the present study was planned to investigate etiological and therapeutic aspects of leukoderma buffaloes. Eighteen buffaloes from 11 villages of Latur District presented with depigmentation of skin formed the material for the present study. Blood samples were processed for complete blood cell count on fully automated haematology cell counter, while serum copper, iron, zinc and ceruloplasmin were estimated on automated biochemical analyzer. The skin biopsy from affected buffaloes was examined for histopathological changes. Nine affected buffaloes were treated with copper sulphate 300 mg /100 kg body weight once daily orally till recovery. An overall incidence of the disease was found to be 0.43%. The characteristic clinical finding was graying of hair and depigmentation of skin on various parts of the body. Haemo-biochemical analysis revealed highly significant (P<0.01) decrease in Hb, PCV, TEC, serum copper, ceruloplasmin and zinc in leukoderma affected buffaloes when compared with healthy control buffaloes. The histoarchitectural studies of leukoderma affected buffalo skin revealed total absence of melanin, melanocytes and melanophores in epidermis. All treated buffaloes clinically cured within 55 to 210 days. It is concluded that leukoderma in buffaloes is caused by copper deficiency and can be successfully treated with copper sulphate.