1,25-dihydroxycholecalciferol [1,25-(OH)2 D3] has been shown to have antiproliferative effects in a wide variety of cancer cell lines. In vivo studies, although often limited by the development of hypercalcemia, have also shown the potential usefulness of 1,25-(OH)2 D3 in inhibiting tumor growth. The potential usefulness of the drug has been hampered by the development of hypercalcemia. This pilot clinical study was designed to evaluate the preclinical results that have shown, locoregional administration of 1,25-(OH)2 D3 in lipiodol can prevent the development of hypercalcemia. Eight patients with refractory HCC were given a single intrahepatic arterial dose (50, 75 or 100 microg) of 1,25-(OH)2 D3 dissolved in 5 ml of lipiodol. Following this, for 4 weeks serum calcium, 1,25-(OH)2 D3, alpha-fetoprotein and a range of biochemical indices were monitored. While, in 3 patients the calcium levels exceeded the normal range, even at these extremely high doses, non of the patients developed grade 3 hypercalcemia. 1,25-(OH)2 D3 administration also led to transient stabilization of serum alpha-fetoprotein in these patients. The data obtained support the hypothesis that, in patients with HCC, locoregional delivery of 1,25-(OH)2 D3 in lipiodol can allow administration of supra-pharmacological doses of the drug without the development of hypercalcemia.