This study was designed to reveal the effects of Fas and FasL polymorphisms of interest on breast cancer risk. A total of 439 patients with breast cancer and 439 controls were enrolled in this study. The genotypes Fas -1377G/A, Fas -670A/G, and FasL -844 T/C were detected by MassARRAY. The protein expressions of estrogen receptor, progesterone receptor, and CerbB-2 were determined by immunohistochemistry. Among the 439 patients, Fas mRNA levels in 22 samples of breast cancer and adjacent normal tissues were detected by real-time polymerase chain reaction, and the soluble Fas and Fas ligand concentrations of 180 patients were measured by enzyme-linked immunosorbent assay. The Fas -1377GA, Fas -1377AA, Fas -670AG, Fas -670GG, and FasL -844TC genotypes were associated with a reduced risk of breast cancer. Haplotype analysis indicated that Fas -1377G/-670A was associated with an increased risk of breast cancer, whereas Fas -1377A/-670A was associated with the opposite effect. Furthermore, gene-gene interaction analysis revealed that the Fas -1377GA/AA (-670AG/GG) and FasL -844CC or TC/TT genotypes were associated with a decreased risk of breast cancer. Meanwhile, -1377GG and -670AA genotypes were associated with higher soluble Fas concentrations than other genotypes. We conclude that Fas and FasL polymorphisms can affect breast cancer risk and that Fas polymorphisms are likely to affect breast cancer risk by regulating the soluble Fas concentration.