Background: Nitazoxanide has not been found to be effective in (Acquired Immunodeficiency Syndrome) patients. Piperazinederivative MMV665917 may potentially be used to treat human cryptosporidiosis, however further investigations are required. Purpose: The aim of this work was to evaluate the effect of piperazine citrate on Cryptosporidium parvum infected mice. Methods: Stool samples would be collected from patients attending Abu-Elrish hospital, showing Cryptosporidium parvum oocyst. One hundred and thirty mice, were selected from (Theodor Bilharz Research Institute). Half of them would take (dexamethasone) for 15 day before infection. Both Nitazoxanide (100mg\kg) and piperazine citrate at different doses (20, 30 & 40 mg\kg) were given to the mice. Assessment of drugs effect was done by parasitological and histopathological assessment. Results: the highest reduction in mean oocysts number of Cryptosporidium parvum was achieved by group treated with combination(nitazoxanide + piperazine 30 ) therapy for 1 week in immunocompromised group (95%) and immunocompetent group (89%) and remarkable regression of histopathological alterations was noticed in ileum of immunocompromised mice treated with combination, when compared with ileum of immunocompromised (positive control) group which showed remarkable histopathological changes exhibited as shortening of the intestinal villi, hyperplasia of goblet cells, inflammatory cells infiltration in the lamina propria , submucosa and edema in the submucosa, multiple Cryptosporidium oocyst .Conclusion: Administration of (piperazine 30+ nitazoxanide) for 7days in immunocompromised group gave the highest reduction rate of mean number of oocysts and remarkable, regression of histopathological alterations.