The molecular and cellular mechanisms that generate the T(h)2 cytokine environment necessary for the maintenance of pregnancy are still not fully understood. We herein show that the human decidua is highly enriched for TCR alpha beta(+)CD161(+) NKT cells. They express non-invariant antigen receptors encoded by diverse TCRV alpha- and V beta-chain gene segments, thereby referred to as non-invariant NKT (non-iNKT) cells. In spite of their diverse TCR expression, they do not recognize fetal allo-antigens but specifically responded to CD1d-transfected cell lines. In contrast to the peripheral blood non-iNKT cells, the decidua-residing non-iNKT cells had a marked T(h)2 bias. In addition, they suppress the mixed leukocyte reaction directed against the paternal antigens. The T(h)2 cytokines have been known to stimulate trophoblast outgrowth and invasion. Thereby, the non-iNKT cells residing in the decidual tissue may have a functionally important interaction with the villous and extravillous trophoblast cells expressing CD1d and may therefore play a pivotal role in successful pregnancy by inhibiting fetal rejection and enhancing placental growth. These findings may reflect one mechanism that is an essential component for the T(h)2 environment necessary for the maintenance of pregnancy.