Background: Gonadotropin-releasing hormone (GnRH) possesses immunostimulatory properties. We have previously demonstrated that GnRH antagonists decrease lymphocyte numbers in an animal model of autoimmune disease. We speculated that the converse might be true, that GnRH administration would increase lymphocyte numbers or alter lymphocyte subsets in an immunodeficiency state. Objective: Our purpose was to test the hypothesis that GnRH agonist would increase IgG and CD4 counts in a rat model of immunodeficiency independently of gonadal steroids. Methods: We used diabetes-prone (DP) BB rats. This model has been characterized to have an AIDS-like lymphocyte profile, with lymphopenia and depressed CD4 counts. Ovariectomized female DP rats were randomized to receive subcutaneous injections with GnRH or vehicle 6 times weekly. DR rats were ovariectomized and treated with vehicle as controls. We performed flow cytometric analysis and complete blood cell counts at baseline, 3.5 weeks, and 7 weeks of treatment. We also measured total serum IgG and luteinizing hormone levels. Results: GnRH administration significantly increased total serum IgG levels in DP rats compared with vehicle. The percentages of CD4⁺ cells in blood were also significantly increased in the GnRH-treated group compared with the vehicle-treated group and compared with baseline. Similarly, the absolute numbers of CD4⁺ positive T cells were increased over controls at 7 weeks. The effects of GnRH were specific for the CD4 subset because there were no significant differences in numbers of CD8⁺ positive cells between the 2 treatment groups. Conclusion: GnRH shows potential utility as an immunostimulatory agent in immunodeficient states manifesting diminished numbers of immunocompetent CD4⁺ T lymphocytes. (J Allergy Clin Immunol 1999;104:653-8.)