Alpha2-HS glycoprotein (AHSG), also known as fetuin-A, is a plasma protein displaying high-affinity interaction with calcium phosphate, by which ectopic vascular calcification is prevented. This investigation has attempted to evaluate the relationship between AHSG polymorphism and serum levels of AHSG and calcium-related parameters. AHSG levels in unrelated individuals were measured by quantitative rocket immunoelectrophoresis and were 581+/-38, 542+/-31, and 494+/-23 mg/l for three major genotypes of AHSG1 homozygotes (n=99), heterozygotes (n=55), and AHSG2 homozygotes (n=22), respectively (differences were significant: P<0.001). The circulating AHSG level was therefore influenced by the genetic polymorphism with the additive reduction in the AHSG2 allele. Statistical analysis of simple and multiple regression models revealed no associations between AHSG levels and serum values of total calcium, albumin-corrected total calcium, and ionized calcium. However, the AHSG levels demonstrated a significant negative correlation with free phosphate levels (P<0.001), indicating that AHSG is a novel determinant of serum phosphate. The AHSG polymorphism is attributable to the hereditary variation of AHSG and phosphate serum levels, which may affect skeletal development and chronic disorders such as vascular calcification.