Scleroderma is a chronic connective tissue disease characterized by excessive collagen synthesis and its deposition in the skin and various internal organs. Immune system abnormalities and disturbances of connective tissue metabolism have been suggested to play a central role in the pathogenesis of scleroderma. 1.25-Dihydroxyvitamin D3 (1.25(OH)2 D3 causes inhibition of fibroblast growth, has a role in controlling collagen synthesis and deposition and has numerous immunoregulatory activities. We assessed the effects of oral 1.25 (OH)2 D3 in the treatment of patients with generalized morphea. Three patients with generalized morphea, entered an open prospective study. They were treated with oral calcitriol (1.25 dyhidroxyvitamin D3) in an oral daily dose of 0.50-0.75 microgram. After the treatment period of 4-6 months, a significant clinical improvement was observed. The mobility of the joints improved, the skin extensibility increased and a substantial improvement of the skin induration. No serious side effects were observed. The improvement persisted after discontinuation of therapy during a follow-up period of one year. The evolution of the patients' condition during the 6 months therapy with calcitriol, suggests that it can be used as a beneficial agent in the treatment of generalized morphea. Double-blind, placebo-controlled trials are needed to assess its therapeutic value and a larger number of patients is desirable.