Susceptibility of three strains of immunodeficient mice to two related microsporidian species Encephalitozoon cuniculi Levaditi, Nicolau et Schoen, 1923 and Encephalitozoon intestinalis (Cali, Kotler et Orenstein, 1993) was compared. While both, severe combined immunodeficient (SCID) and interferon-gamma knock-out (IFN-γ KO) mice, succumbed to either intraperitoneal (i.p.) or peroral (p.o.) (natural) infection with both parasites, only i.p. infection with E. cuniculi killed interleukin-12 knock-out (IL-12 KO) mice. IFN-γ KO mice died earlier than SCID mice. Adoptive transfer of naive splenocytes from IFN-γ KO mice did not protect the SCID mice from a lethal infection with either of the Encephalitozoon species. However, reconstituted mice survived significantly longer (P<0.05), thus indicating the role of IFN-γ produced by host NK cells in the development of mechanisms of anti-microsporidial protective immunity. Non-lethal outcome of the infection always correlated with the increase in CD8+ T lymphocyte subpopulation. Both E. intestinalis-infected IFN-γ KO and IL-12 KO mice produced comparable levels of specific antibodies, suggesting that antibodies did not protect IFN-γ KO mice from lethal infection.