Weight reduction induces bone loss by several factors, and the effect of higher protein (HP) intake during caloric restriction on bone mineral density (BMD) is not known. Previous study designs examining the longer-term effects of HP diets have not controlled for total calcium intake between groups and have not examined the relationship between bone and endocrine changes. In this randomized, controlled study, we examined how BMD (areal and volumetric), turnover markers, and hormones [insulin-like growth factor 1 (IGF-1), IGF-binding protein 3 (IGFBP-3), 25-hydroxyvitamin D, parathyroid hormone (PTH), and estradiol] respond to caloric restriction during a 1-year trial using two levels of protein intake. Forty-seven postmenopausal women (58.0 ± 4.4 years; body mass index of 32.1 ± 4.6 kg/m(2) ) completed the 1-year weight-loss trial and were on a higher (HP, 24%, n = 26) or normal protein (NP, 18%, n = 21) and fat intake (28%) with controlled calcium intake of 1.2 g/d. After 1 year, subjects lost 7.0% ± 4.5% of body weight, and protein intake was 86 and 60 g/d in the HP and NP groups, respectively. HP compared with NP diet attenuated loss of BMD at the ultradistal radius, lumbar spine, and total hip and trabecular volumetric BMD and bone mineral content of the tibia. This is consistent with the higher final values of IGF-1 and IGFBP-3 and lower bone-resorption marker (deoxypyridinoline) in the HP group than in the NP group (p < .05). These data show that a higher dietary protein during weight reduction increases serum IGF-1 and attenuates total and trabecular bone loss at certain sites in postmenopausal women.