This study tested the hypothesis that estrogen enhances axonal sprouting in the hippocampal formation in the female mouse. The entorhinal cortex was unilaterally lesioned with ibotenic acid in control mice and in ovariectomized mice that were treated with a high dose of, a moderate dose of, or zero estrogen supplementation pellets. Four weeks later the density of staining for synaptophysin immunoreactivity and acetylcholinesterase (AChE) histochemistry was measured in the molecular layer of the dentate gyrus. In control mice, lesions of the lateral part of the entorhinal cortex increased synaptophysin and acetylcholinesterase staining (i.e., indicative of axonal sprouting) in the outer one-third of the molecular layer of the dentate gyrus. Mice receiving high and moderate estrogen supplementation displayed the same sprouting response; however, in ovariectomized mice the sprouting response was significantly reduced (to nearly nothing). Thus, in ovariectomized compared with control mice the lesion-induced sprouting response is severely blunted, and this effect is reversed by estrogen supplementation. Together, these findings suggest that estrogen plays a prominent role in promoting neuronal plasticity and remodeling in the dentate gyrus.