We describe a 7-month-old boy who manifested severe hypercalcemia associated with mesenchymal neoplasm. A huge hypervascular tumor on the neck had been detected in prenatal ultrasonography. Surgical removal of the entire tumor at birth was not indicated, because the tumor was diagnosed as hemangioma. Chemotherapy and radiotherapy were attempted, but there was no effect on tumor growth. When the infant was 6 months old, the serum calcium level increased rapidly, associated with the expansion of the tumor. Hypophosphatemia due to phosphaturia was also observed. Serum PTH was undetectable, whereas the serum concentration of carboxyl-terminal (C-terminal) fragments of PTH-related protein (PTH-rP) was markedly elevated. Northern blot analysis and immunostaining demonstrated the expression of PTH-rP in the tumor. The tumor was transplantable to nude mice and caused elevation of circulating PTH-rP in the animals. Histological examination of the patient's bone revealed an increased number of osteoclasts. These findings were consistent with humoral hypercalcemia of malignancy caused by the excess production of PTH-rP. The tumor was identified histologically as infantile fibrosarcoma, which has not been reported as a cause of humoral hypercalcemia of malignancy to date. The expression of PTH/PTH-rP receptor messenger ribonucleic acid was detected in the tumor by the RT-PCR, suggesting that PTH-rP may have exerted its effect in the tumor in an autocrine/paracrine manner. In addition to the systemic effect of PTH-rP manifested as hypercalcemia, the PTH-rP secreted from the neoplasm could have been a local factor involved in the growth of the tumor.