Absence of cyclooxygenase (COX)-2 activity in vitro reduces differentiation of both bone-forming and bone-resorbing cells. To examine the balance of COX-2 effects on bone in vivo, we studied COX-2 knockout (KO) and wild-type (WT) mice. After weaning, KO mice died 4 times faster than WT, consistent with reports of progressive renal failure in KO mice. Among KO mice killed at 4 mo of age, some had renal failure with marked secondary hyperparathyroidism, but others appeared healthy. On the assumption that renal failure was not inevitable in COX-2 KO mice and that phenotypic differences might increase with age, we studied KO mice surviving to 10 mo of age with serum creatinine similar to WT mice. In 10-mo old male KO mice, serum calcium and parathyroid hormone (PTH), but not phosphorus, levels were increased compared with WT mice. 1,25(OH)₂D₃ levels were markedly elevated in KO mice. Skeletal analysis showed small non-significant decreases in cortical bone density by BMD and either an increase (distal femur, µCT) or no difference (distal femur, static histomorphometry) in trabecular bone density in KO mice. There was a trend toward increased percent osteoblastic and osteoclastic surface, and on dynamic histomorphometry, the rates of trabecular bone formation (BFR/BS) and mineral apposition (MAR) were increased in KO mice relative to WT mice. Similar trends were observed for most parameters in 10- mo old female COX-2 KO mice. However, BFR/BS and MAR were increased in 10-mo old WT females compared with males and did not increase further in female KO mice. These data suggest that COX-2 KO mice with intact renal function have primary hyperparathyroidism and that effects of increased PTH and 1,25(OH)₂D₃ to increase bone turnover may compensate for the absence of COX-2.