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Microsporidia are a group of obligate, intracellular, spore-forming eukaryotic pathogens, which predominantly infects immunocompromised individuals worldwide. Encephalitozoon spp. is one of the most prevalent microsporidia known to infect humans. Host immune system plays a major role in combating pathogens including Encephalitozoon spp. infecting humans. Both innate and adaptive arms of host immune system work together in combating Encephalitozoon infection. Researchers are conducting studies to elucidate the role of both arms of immune system against Encephalitozoon infection. In addition to cell-mediated adaptive immunity, role of innate immunity is also being highlighted in clearance of Encephalitozoon spp. from host body. Therefore, the current review will give a clear and consolidated update on the role of innate as well as adaptive immunity in protection against Encephalitozoon spp.