Osteopontin (OPN) plays an important role in the development and progression of some tumors. The polymorphisms of OPN probably change its expression and contribute to interindividual differences of susceptibility to some cancers. The purpose of the present study was to explore the association of rs9138 (+1239; 3'UTR: 3'untranslated regions) and rs1126616 (+750; exon 7) polymorphisms located in the OPN gene with colorectal carcinoma (CRC) susceptibility and to investigate the correlation of the polymorphisms, plasma levels of the OPN protein, clinicopathologic parameters, tumor markers, and lipid. The genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. The plasma levels, tumor markers, and lipid were measured by enzyme-linked immunosorbent assay. The results indicated that genotype AA and AC of rs9138 and CC and CT of rs1126616 were associated with increased risk of CRC. The allelic frequencies of rs9138A, rs1126616C, and the haplotype (A-C) were associated with increased risk of CRC. Although there was no significant difference of plasma levels in various genotypes, increased plasma protein expression in CRC patients compared with controls was found. Our results suggested that the rs9138 and rs1126616 of OPN were associated with CRC risk, and the OPN protein in plasma may be a potential tumor marker of CRC.