-Parathyroid hormone-related protein (PTHrP) is a factor associated with normal development and physiology of the nervous, cardiovascular, immune, reproductive, and musculoskeletal systems in higher vertebrates. It also stimulates whole body calcium uptake in sea bream (Sparus auratus) larvae with an estimated 60% coming from intestinal uptake in seawater. The present study investigated the role of PTHrP in the intestinal calcium transport in the sea bream in vitro. Unidirectional mucosal-to-serosal and serosal-to-mucosal 45 Ca fluxes were measured in vitro in duodenum, hindgut, and rectum mounted in Ussing chambers. In symmetric conditions with the same saline, bathing apical and basolateral sides of the preparation addition of piscine PTHrP 1-34 (6 nM) to the serosal surface resulted in an increase in mucosal to serosal calcium fluxes in duodenum and hindgut and a reduction in serosal to mucosal in the rectum, indicating that different mechanisms are responsive to PTHrP along the intestine. In control asymmetric conditions, with serosal normal and mucosal bathed with a saline similar in composition to the intestinal fluid, there was a net increase in calcium uptake in all regions. The addition of 6 nM PTHrP 1-34 increased net calcium uptake two-to threefold in all regions. The stimulatory effect of PTHrP on net intestinal calcium absorption is consistent with a hypercalcemic role for the hormone. The results support the view that PTHrP, alone or in conjunction with recently identified PTH-like peptides, counteracts in vivo the hypocalcemic effects of stanniocalcin. fish; intestine; hypercalcemia IN HIGHER VERTEBRATES, calcium homeostasis is controlled largely by the interplay of the hypocalcemic hormone calcitonin, produced in the C cells of the thyroid gland, and the hypercalcemic parathyroid hormone (PTH), produced in the parathyroid gland. The parathyroid gland first appears as an isolated and functional gland in amphibians (6), and its formation is controlled by the transcription factor Gcm-2. In fish, Gcm-2 controls internal gill bud formation (18,28), and its coexpression with PTH transcripts has led to the suggestion that the parathyroid gland derived from the fish gill (28). However, coexpression of PTH and Gcm-2 has not been confirmed (17).Early studies (29) suggested that the pituitary gland of fishes contains a hypercalcemic factor related to, but distinct from, PTH. Furthermore, immunohistochemical studies indicated the presence in the pituitary and other tissues of several teleosts of parathyroid hormone-related protein (PTHrP) (7,20), a factor that shares with PTH hypercalcemic activity and a common receptor (25). The first fish PTHrP gene and cDNA were cloned in the puffer fish, Takifugu rubripes (31), and in the sea bream, Sparus