Objective: To determine the genotoxic effects of clomiphene citrate (CC) on rat reticulocytes in vivo. Methods: In this prospective, randomized, controlled study, rats were each assigned randomly to the CC 50, CC 100, CC 200, or control group and were given repeat doses of 0.16, 0.32 or 0.64 mg CC, or normal saline, respectively. Each study group received its CC dose in 2 ml of saline intraperitoneally for 5 days, while the control group received only 2 ml of saline. Each treatment cycle was repeated six times. Six months later, the rats were euthanized. Bone marrow tissues were removed, and pluripotent reticulocyte cells with micronuclei, nuclear buds, and binuclear abnormalities were analyzed using an in situ micronuclei assay under light microscopy. The proportion of micronucleated erythrocytes was measured. Results: Fewer cells with nuclear buds and binuclear abnormalities were detected in the CC 50 group and controls. The CC 100 and 200 groups had significantly (p < 0.05) more nuclear buds and binuclear abnormalities compared with the CC 50 group and controls in the cytogenetic analysis of bone marrow stem cells. Conclusion: In rats, the micronucleus genotoxicity assay suggests a dose-dependent CC effect on genomic instability in bone marrow stem cells in vivo. Copyright (c) 2006 S. Karger AG, Basel.