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Decidual and peripheral blood lymphocyte subsets were studied for their expression of CD44, L-selectin (Leu-8), CD54, and CD11b cell adhesion molecules (CAM). Most CD3+, CD4+, CD8+, and CD56+ cells in decidua were L-selectin- and CD44+, i.e., had a phenotype consistent with mucosa-homing preference of decidual lymphocytes (DL). We observed trimodal staining of decidual and peripheral blood CD56+ and CD8+ cells with anti-CD44 monoclonal antibody; negative, weakly positive, and brightly positive subpopulations were evident. Relatively high levels of CD44-negative CD56+ and CD8+ cells were found in decidua. Most decidual T and natural killer (NK) cells expressed high amounts of the CD54 molecule. Substantially higher numbers of CD3+, CD4+, and CD8+ cells in decidua bore CD11b, whereas the percentage of CD11b-positive NK cells was significantly lower in decidua, compared with that seen in peripheral blood. As opposed to peripheral blood lymphocytes (PBL), phorbol 12-myristate 13-acetate (PMA) stimulation of decidual NK cells elicited a rapid increase in the numbers of CD11b-positive cells but not increased fluorescence intensity of CD11b on the stained cells. The CD54 molecule was also up-regulated on decidual and peripheral blood NK cells but only after 15 hr of stimulation with PMA. In contrast to peripheral blood cells, activation of decidual mononuclear cells by K562 did not lead to an augmentation of the CD11b and CD54 expression on NK lymphocytes. These findings suggest that expression of CAM on DL is regulated in a manner different from that of PBL, and CAM expression may be adapted to accommodate placentation in human beings. The interaction of lymphocytes by means of antigen-independent cell-cell adhesion could be essential for the development of the placenta and the regulation of the local maternal immune response to the genetically foreign fetus.