To assess the efficacy of prostaglandin E₂ (PGE₂) in augmenting cortical bone mass, graded doses of PGE₂ were subcutaneously administered for 30 days to seven-month old sham-ovariectomized (SHAM) and ovariectomized (OVX) rats. Both groups were operated at three months of age. Histomorphometric analyses of double fluorescent labeled tibial shafts were performed on basal control, OVX, and SHAM rats treated with 0, 0.3, 1, 3, and 6 mg PGE₂/kg/d for 30 days. Baseline aging data showed increased cortical tissue and cortical bone area and reduced bone formation parameters at the periosteal and endocortical bone envelopes between three and eight months of age. The tibial shafts of OVX rats compared to SHAM controls showed elevated periosteal mineral apposition rate and endocortical bone formation parameters. PGE₂ administration to OVX and SHAM rats increased cortical bone by the addition of new circumferential bone on the endocortical and periosteal surfaces, as well as woven cancellous bone in the marrow region. Stimulated osteoblastic recruitment and activity enhanced bone formation at all bone surfaces. The new bone was both lamellar and woven in nature. PGE₂ treatment also activated intracortical bone remodeling (not seen in untreated eight-month old rats), creating a porous cortex. Thus, PGE₂ administration activated cortical bone modeling in the formation mode (A→F), as well as intracortical bone remodeling (A→R→F). PGE₂ administration to OVX rats resulted in more intracortical bone remodeling, periosteal bone formation, and new cancellous bone production than observed in PGE₂ treated controls. The findings that PGE₂ administration to OVX and intact female rats increases cortical bone mass, coupled with observations that mouse, rat, dog, and man respond similarly to PGE₂, suggest that PGE₂ administration may be useful in the prevention and treatment of postmenopausal osteoporosis.