Prostaglandins (PGs) are key regulatory factors that affect bone metabolism. Prostaglandin E(2) (PGE(2)) regulates bone resorption and bone formation. Prostacyclin (PGI(2)) is one of the major products derived from arachidonic acid by the action of cyclooxygenase and PGI(2) synthase (PGIS). Unlike PGE(2), there are few reports about the role of PGI(2) in bone regulation. Therefore, we investigated the potential effect of PGI(2) on bone metabolism. We used PGIS knockout (PGIS(-/-)), PGIS heterozygous (PGIS(+)(/-)), and wild-type mice to investigate the role of PGI(2). Notably, PGIS(-/-) mice gradually displayed an increase in trabecular bone mass in adolescence. Adult PGIS(-/-) mice showed an increase in trabecular bone volume/tissue volume. Histomorphometric analysis showed that PGIS(-/-) mice displayed increases in both bone formation and bone resorption parameters. Levels of serum osteocalcin and C-telopeptides were increased in adult PGIS(-/-) mice. Furthermore, the increased bone mass patterns were rescued in PGIS(-)/(tg) mice. In conclusion, adult PGIS(-/-) mice displayed an overall increase in the levels of both bone formation and bone resorption parameters, which suggests that PGI(2) deficiency accelerates high bone turnover activity with a greater increase in bone mass in aging. These results indicated that PGI(2) may contribute to the maintenance of normal bone mass and micro-architecture in mice in age-dependent manner. Our findings demonstrate for the first time that PGI(2) is involved in bone metabolism in vivo.