Addition of bisphosphonates to standard treatment of multiple myeloma (MM) decreases bone pain and skeletal events without influencing bone healing. Calcitriol, besides its established effects on bone remodeling and calcium metabolism, has both immunoregulatory and cell differentiating effects in vitro and in vivo. Moreover, low serum calcitriol has been reported in MM. We tested the effects of supportive treatment with calcitriol and pamidronate on bone disease in two stage-III-B MM patients with diffuse bone involvement, normal serum calcium, and low serum calcitriol. Complete blood counts, serum calcium, creatinine, quantitative serum and urine immunoglobulins, and biochemical indices of bone turnover, serum calcidiol, calcitriol, parathyroid hormone, skeletal radiographs, and bone mineral density by dual x-ray absorbtiometry were measured every 1-6 months for 16 months in the first patient and 7 months in the second patient. Both patients showed a dramatic improvement of MM activity and in bone disease documented by serial radiographs in the first patient and by increased bone mineral density (approximately 15%) in the second. The reduced serum calcitriol in both patients and the elevated parathyroid hormone observed in the first patient before treatment returned to normal. Supportive treatment with pamidronate does not induce bone healing in MM. Therefore, the results observed with the addition of calcitriol suggest that this hormone may have contributed to the apparent arrest of the progression of MM and caused stimulation of bone healing.