Background: The malignant ovine theileriosis is caused by Theileria lestoquardi, which is highly pathogenic in sheep. Theileriosis involves different organs in ruminants. The aim of the study is to understand the immunopathogenesis of the malignant ovine theileriosis by measurement of concentration changes of proinflammatory cytokines (IL-6, TNF-α, IFNγ) and IgG during an ovine experimental theileriosis. Materials and Methods: During an experimental study, seven healthy Baluchi sheep (4 females and 3 males) about 6-8 months were infected with T.lestoquardi by feeding of infected unfed ticks on the sheep ears. The infected sheep clinically examined during the study and the blood samples were collected on days 0, 5, 10, 17, and 21. Results: All infected animal showed a significant temperature rise on day 3 and 4.The common symptoms in all infected sheep included fever, emaciation, enlarged prescapular lymph nodes, anemia, and cardiac dysfunction. The piroplasm and schizont forms were observed in the blood and lymph node smears on days 6–11 and 3–5 post infection, respectively. The parasitemia was lower than 1% and the schizont was observed in enlarged prescapular lymph nodes. A significant reduction in the number of WBC, neutrophil, and lymphocyte was observed from day 10 to day 21. The concentration of all cytokines and IgG increased until the day 10 and after that slightly decreased until the day 21 post infection. Conclusion: The clinical sign of experimental T.lestoquardi infection of sheep is characterized by high fever, lymph nodes enlargement, nasal discharge, anorexia, cachexia, and death. The T.lestoquardi infection is caused neutropenia and lymphopenia from day 10 to end of the study and the proinflammatory cytokines and IgG increased from day 0 to 10 and then slightly decreased to day 21

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