Unexplained recurrent spontaneous abortion (URSA) is an alloimmune disease associated with the failure of fetal-maternal immunologic tolerance in which the regulatory T lymphocytes (Treg) play a pivotal role. It is well known that Forkhead box P3 (Foxp3) is a crucial regulatory factor for the development and function of Treg cells. It has also been established that deficiency of the Foxp3 gene suppresses the regulatory function of Treg cells. To determine if functional polymorphisms at the Foxp3 loci are associated with URSA in humans, we genotyped four common polymorphisms of Foxp3 gene in 146 unrelated URSA patients and 112 healthy women. The results showed that rs3761548A/C and rs2232365A/G polymorphisms were significantly associated with URSA. Additionally, we found that the allelic distribution of rs5902434 del/ATT in URSA group was slightly different from that in the control group. We conclude that functional polymorphisms of the Foxp3 gene may confer an important susceptibility to URSA in the Chinese Han population, probably by altering Foxp3 function and/or its expression.