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Stephanofilariasis or humpsore is a chronic parasitic dermatitis of cattle. Various treatment regimens were attempted in the past but were found to be partially effective. Here, we claim a successful treatment regime using an FDA-approved macrocyclic lactone, a piperazine derivative, and an herbal preparation. Twenty-four cattle (18 affected and 6 unaffected) were selected and divided into Gr 1: positive control (infected without treatment; n = 6), Gr 2: treatment group (infected with treatment with ivermectin; n = 6), Gr 3: treatment group (infected with treatment with tri-model therapy including ivermectin, diethylcarbamazine citrate, and an herbal ointment, n = 6), and Gr 4: negative control (non-infected animals; n = 6). In Gr 2 and Gr 3, treatment to the ailing animals were given for 30 days. Lesion was significantly reduced in day 15 of post-treatment and completely healed on day 30 of post-treatment in Gr 3. Tri-model therapy recorded significant improvement in the surface area of the sore as compared to ivermectin administration alone. Antioxidants were increased and malondialdehyde (MDA) and cortisol concentrations were decreased significantly (p < 0.05) in Gr 3 than in untreated control group at day 14, 21 and 28. Histopathological changes in infected animals were characterized by parakeratotic hyperkeratosis along with presence of nucleated keratinocytes. There were infiltrations of polymorphonuclear cells specially eosinophils along with a few monomorphonuclear cells. Microfilarial organism was observed beneath the epidermis, which was surrounded by fibrocytes and infiltrated cells. In the tri-model-treated animal after recovery, the skin revived a normal architecture. Therefore, tri-model therapy has the potential to cure humpsore. Full article