As cocaine may affect progression of the Human Immunodeficiency Virus (HIV) infection to Acquired Immune Deficiency Syndrome (AIDS), we used a murine model of AIDS (MAIDS) induced by LP-BM5 murine leukemia virus to examine cocaine's possible role as a cofactor for secondary parasitic infections. Dissimilarities between the sexes were observed both in the absence and presence of the cocaine. The retrovirus-infected female mice had a much higher rate of Cryptosporidiosis than the retrovirus-infected male mice. Female, but not male, retrovirus-infected mice showed approximately 20-fold more Cryptosporidium per villus section than controls. Compared to respective gender controls, male and female animals infected with the retrovirus infection manifested a heightened Cryptosporidium oocysts count regardless of cocaine treatment. Overall, female groups incurred a higher incidence of infection compared to respective male groups. To determine the role of cocaine, groups of male and female C57BL-6 mice of similar age were treated with cocaine for 4 weeks followed by termination. Cocaine synergized with retrovirus infection in female mice to cause a 30-fold increase in the number of oocyst present. The spleen size and weight of female mice was significantly greater than uninfected controls or male mice. However, due to the very slow progression to murine AIDS in the males, parasite resistance was retained, including in cocaine treated C57BL-6 mice. Thymus cell number in the retrovirus-infected female mice decreased significantly in comparison to uninfected female controls. Continued resistance to the parasite in male mice and its loss in female mice was due to the rate of immunosuppression and thus development of retrovirus-induced murine AIDS.