PTH is the only currently available anabolic therapy for osteoporosis. In clinical practice, the skeletal response to PTH varies and because therapy is limited to 2 yr, approaches to maximize the therapeutic response are desirable. Rac2 is a small GTPase that is expressed only in hematopoietic tissue. Rac2−/− mice have a slight increase in bone mass and osteoclasts isolated from these animals have reduced basal resorptive activity and reduced chemotaxis. To evaluate the anabolic response to PTH in Rac2−/− mice, we treated 18 Rac2−/− and 17 control, age-matched wild-type animals once daily for 28 d with 80 ng/g body weight of h(1–34)PTH. Treatment resulted in significantly greater increments in spinal, femur, and total bone density in the Rac2−/− as compared with wild-type animals. Microcomputed tomography analysis demonstrated greater increases in trabecular thickness and cortical thickness in the knockout mice. Interestingly, histomorphometric analysis showed an equivalent increase in osteoblast and osteoclast number in response to PTH treatment in both groups of animals. However, as judged by changes in serum markers, the resorptive response to PTH was impaired. Thus, telopeptide of type 1 collagen was 15.9 ± 6.9 ng/ml after PTH treatment in the knockout animals and 26.8 ± 11.1 ng/ml in the PTH-treated wild-type group. In contrast, serum aminoterminal propeptide of type 1 collagen and osteocalcin were equivalent in both groups. We conclude that, in the genetic absence of Rac2, the anabolic response to PTH is increased. This appears to be due to attenuated resorptive activity of osteoclasts.