In rabbits bearing the prostaglandin-producing VX2 carcinoma, the plasma concentration of 13,14-dihydro-15-keto-PGE2 (PGE2-M) was elevated within one week after tumor implantation and preceded the development of hypercalcemia. Both the rate of rise and magnitude of the increase were greater for the metabolite than for PGE2; at the time of peak hyercalcemia (about 4 to 5 weeks after tumor implantation), the increase over basal in plasma PGE2-M was about 75 fold whereas it was previously shown that the increase in PGE2 was less than 2 fold. Indomethacin, which inhibits PGE2 synthesis in VX2 cells in culture, lowered in parallel plasma calcaium and PGE2-M in tumor-bearing rabbits. Administration of hydrocortisone to rabbits bearing the VX2 tumor prevented the development of hypercalcemia when given at the time of tumor implantation and reversed the elevated plasma calcium in previously untreated animals; the steroid hormone also lowered plasma concentrations of PGE2-M. These findings are consistent with our hypothesis that the hypercalcemic syndrome in VX2 tumor-bearing rabbits is due to the secretion of PGE2 by the tumor.