Fetuin-A prevents tissue calcification by forming soluble complexes with calcium and phosphate. A pathological depletion of serum fetuin-A has been observed in children on dialysis or after renal transplantation but knowledge on physiologic age-related changes in serum fetuin-A is limited. We prospectively evaluated serum fetuin-A in 133 infants and children, ranging from very low birth weight infants to adolescents. Highest serum fetuin-A levels were present between 23 and 30 wk of gestation (1 +/- 0.33 mg/mL). Thereafter, the values decreased. This decrease was linked to biological rather than chronological age. At 32 to 36 and 37 to 40 wk of gestation, the serum fetuin-A concentration was 0.63 +/- 0.26 and 0.63 +/- 0.21 mg/mL, respectively. Thereafter, the concentrations remained stable until adolescence at 0.58 +/- 0.12 mg/mL. Intercurrent infections were associated with a transient decrease of serum fetuin-A levels. The high serum fetuin-A concentrations in preterm children suggest that fetuin-A is of high physiologic impact for the fetal and the preterm-born organism, showing extensive tissue formation. This might point to a new mechanism contributing to organ damage in these patients, comparable with children on dialysis.