Osteopontin (OPN) is a secreted glycoprotein demonstrated to play an important role in inflammation. Transforming growth factor beta and a related signalling pathway have been implicated in control of OPN secretion. We examined the relationship between transforming growth factor beta receptor-1 and -2 (TGFBR1 and 2) single nucleotide polymorphisms (SNP) and serum OPN in 296 men from the Health in Men Study. Serum concentrations of OPN and 58 SNPs for TGFBR1 and 2 were assessed. One SNP in TGFBR2 was associated with serum OPN (TGFBR2 g.20690C>T, SNP ID rs4522809, P = 0.0007) after adjusting for multiple testing. This study suggests that polymorphism in TGFBR2 are associated with altered secretion of OPN, supporting a role for transforming growth factor beta in OPN production.