BACKGROUND: An increased prevalence of low bone mineral density (BMD) has been reported in patients with major depressive disorder (MDD), mostly women. METHODS: Study recruitment was conducted from July 1, 2001, to February 29, 2003. We report baseline BMD measurements in 89 premenopausal women with MDD and 44 healthy control women enrolled in a prospective study of bone turnover. The BMD was measured by dual-energy x-ray absorptiometry at the spine, hip, and forearm. Mean hourly levels of plasma 24-hour cytokines, 24-hour urinary free cortisol, and catecholamine excretion were measured in a subset of women. We defined MDD according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). RESULTS: The prevalence of low BMD, defined as a T score of less than -1, was greater in women with MDD vs controls at the femoral neck (17% vs 2%; P = .02) and total hip (15% vs 2%; P = .03) and tended to be greater at the lumbar spine (20% vs 9%; P = .14). The mean +/- SD BMD, expressed as grams per square centimeters, was lower in women with MDD at the femoral neck (0.849 +/- 0.121 vs 0.866 +/- 0.094; P = .05) and at the lumbar spine (1.024 +/- 0.117 vs 1.043 +/- 0.092; P = .05) and tended to be lower at the radius (0.696 +/- 0.049 vs 0.710 +/- 0.055; P = .07). Women with MDD had increased mean levels of 24-hour proinflammatory cytokines and decreased levels of anti-inflammatory cytokines. CONCLUSIONS: Low BMD is more prevalent in premenopausal women with MDD. The BMD deficits are of clinical significance and comparable in magnitude to those resulting from established risk factors for osteoporosis, such as smoking and reduced calcium intake. The possible contribution of immune or inflammatory imbalance to low BMD in premenopausal women with MDD remains to be clarified.