Objective To evaluate the influence of Eperythrozoon infection on human and mouse erythrocytes and to explore the pathogenesis of Eperythrozoonosis. Methods The specific gene fragment of Eperythrozoon was detected by polymerase chain reaction (PCR) from the venous blood samples of five patients infected with Eperythrozoon. The complement receptor type I (CD35) expression on erythrocytes of these five patients was determined by flow cytometry. Thereafter, the Eperythrozoons were purified from human samples and injected into mice through the tail veins. Blood smear microscopy, PCR and transmission electron microscopy were used to assure the successful infection. The hematological indicators of human and mice, such as red blood cell (RBC) count,hemoglobin (Hb) content, hematocrit and superoxide dismutase (SOD) were evaluated. All results were analyzed by t test. Results More than 80% of treated mice were confirmed to be infected with Eperythrozoon successfully. A fragment of 801 bp specific gene of Eperythrozoon was detected by PCR in samples from both infected patients and infected mice, which were not detected in samples from healthy control people or control mice. CD35 was highly expressed on the erythrocytes of infected patients, but not expressed on the erythrocytes of infected mice. Both RBC counts and Hb content dramatically decreased in infected patients and infected mice. Hematocrit and the activity of SOD also slightly decreased in infected patients and infected mice. Conclusions Eperythrozoon can spread between human and mice and destroy erythrocyte structure. Eperythrozoon can upregulate CD35 expression in human, but there is no CD35 expression in mice.