MHC class I genes are important in the regulation of cyst number in mice perorally infected with Toxoplasma gondii. Since human MHC class I molecules may be capable of functioning as restriction elements in mice, to determine whether class I genes also control outcome of T. gondii infection for humans, a transgenic mouse model was developed using human class I genes in mice. Human HLA-B27 and Cw3 transgenic mice, with the cyst-susceptible B10 mouse background, were tested for resistance to cyst formation after peroral infection with the Me49 strain of T. gondii. Introduction of the B27 gene into susceptible mice made them even more susceptible to T. gondii brain cyst formation. In contrast, HLA-DB27 transgenic mice that have a substitution of the alpha 3 portion of the human class I molecule with the alpha 3 portion of the mouse Kd molecule had the same number of brain cysts as susceptible B10 control mice when perorally infected. Similarly, HLA-Cw3 transgenic mice had the same number of brain cysts as the susceptible B10 controls. These results indicate that the interaction between CD8 on mouse T cells and the human class I molecule in transgenic mice does not always occur, and sometimes may hinder a normal response. Furthermore, B27 and Cw3 transgenes did not generate resistance to cyst formation in infection by T. gondii.