Context Pregnancy- and lactation-associated osteoporosis (PLO) is a rare condition characterized by fragility fractures, mostly vertebral, during the third trimester of pregnancy or the early postpartum period. Objective The aim of this study was to evaluate bone microarchitecture in women with PLO to better understand the pathophysiology of this disease. Methods In this retrospective study, we included women with PLO referred to our bone center between November 2007 and July 2012. We assessed bone mineral density (BMD) by dual-energy x-ray absorptiometry, bone turnover markers, and bone microarchitecture by high-resolution peripheral quantitative computed tomography. Results were compared with a control group of healthy lactating women. Results Of the 7 primiparous patients with PLO, 6 suffered vertebral fractures and 1 developed a hip fracture during the seventh month of gestation. Fractures occurred within the eighth month of pregnancy and the fourth month post partum; vertebral fractures were multiple in 85.7%. Major or minor risk factors for osteoporosis were present in 86% of our patients. Trabecular density, number, and thickness were 34%, 20% and 22% lower than controls (P < .01, P = .01, and P = .01, respectively). Cortical parameters were also deteriorated but to a lesser extent. Conclusion In comparison with healthy lactating women, patients with PLO presented severe deterioration of bone trabecular and cortical microarchitecture. This significant compromise may explain the occurrence of multiple fractures in these otherwise healthy young women. Further prospective studies are needed to determine whether bone microarchitecture might be able to be restored in the future.