Osteocalcin is a vitamin K-dependent protein, synthesized in bone, which can be detected in serum. We have measured circulating osteocalcin levels in 10 patients with xlinked hypophosphatemia (XLH) and in 6 patients with autosomal recessive vitamin D dependence (ARVDD) who started 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] therapy. Patients with XLH were studied before and after 7–12 months of therapy that included 1,25-(OH)2D3 (10–72 ng/kg·day) and oral phosphate. Serum osteocalcin rose from 28 ± 12 to 52 ± 12 ng/ml (mean ± SE; P < 0.01) in concert with improvements in biochemical status and bone mineralization. Vitamin D therapy was withdrawn for 2 weeks from patients with ARVDD. The vitamin D-deplete status was evidenced by low 1,25-(OH)2D3 levels (12 ± 2 pg/ml; n = 6). After 1 week of therapy with 1,25-(OH)2D3) serum calcium rose from 9.03 ± 0.21 to 9.67 ± 0.25 mg/dl (P < 0.002), while serum phosphorus and alkaline phosphatase remained unchanged. Serum osteocalcin rose from 35 ± 7 to 83 ± 32 ng/ml (P < 0.05). At 3 weeks, serum calcium remained elevated (9.63 ± 0.18 ng/dl) over control levels (P < 0.01); phosphorus and alkaline phosphatase were still unchanged. Serum osteocalcin rose to 114 ± 42 ng/ml, significantly greater than values at 1 week (P < 0.05). Thus, serum osteocalcin increases after 1,25-(OH)2D3 therapy in both ARVDD and XLH. (J Clin Endocrinol Metab56: 1063,1983)