Background: The safety of using reduced calcium dialysate (RDC) in hemodialysis (HD) patients is controversial due to related changes in bone metabolism. In the present study we investigated whether an 18-month treatment period with RDC may induce significant changes in calcium-phosphorus product (CaxP), bone metabolism, and components of the insulin-like growth factor (IGF) system in HD patients. Study Design: In this prospective study, 13 HD patients with biochemical signs of diminished or low-normal bone turnover and high CaxP due to high serum calcium level were treated by lowering dialysate calcium from 3.5 to 2.5 mEq/l for 18 months. By specific immunometric assays, serum levels of intact parathyroid hormone (PTH), bone alkaline phosphatase (B-ALP), pyridinoline (PYR), desoxypyridinoline (D-PYR), 25-OH-vitamin D<sub>3</sub> (25-vit D<sub>3</sub>), 1,25-(OH)<sub>2</sub>-vitamin D<sub>3</sub> (1,25-vit D<sub>3</sub>), free IGF-I, IGF-II, and IGF-binding protein (IGFBP)-1 to -6 were measured. Results: CaxP decreased significantly from 5.62 (baseline) to 3.95 mmol<sup>2</sup>/l<sup>2</sup> (at 18 months), whereas PTH increased from 81 ± 57 pg/ml at baseline to 236 ± 188 at 12 months (p < 0.01), remaining in this range thereafter. Parameters of bone resorption (PYR) as well as formation (B-ALP) significantly increased during RDC, with peak levels after 12 months. Despite increasing doses of oral alfacalcidol, levels of 25-vit D<sub>3</sub> and 1,25-vit D<sub>3</sub> subsequently declined during RDC. In parallel with the changes in bone markers, free IGF-I levels decreased (baseline: 1.9 ± 0.9 ng/ml, after 18 months: 1.1 ± 0.7; p < 0.01). The decline of free IGF-I correlated with decreasing levels of IGFBP-3 and increasing levels of IGFBP-1/-4. Conclusion: The treatment with RDC effectively lowered CaxP and stimulated bone formation and resorption. The different changes in bone markers and IGF system components mirror the complex effects on bone metabolism.