We have analyzed the morphological characteristics of human T lymphocytes bearing CD3-associated T cell receptor (TcR) gamma and delta chains. BB3 and delta-TCS1 monoclonal antibodies (mAb) were used to identify two distinct, nonoverlapping populations of TcR gamma/delta + cells which express the products of V delta 2 and V delta 1 gene segments, respectively. In the peripheral blood, most V delta 1+ (delta TCS-1+) lymphocytes express the non-disulfide-linked form of receptor whereas V delta 2+ (BB3+) cells express the disulfide-linked form. The majority of cloned TcR gamma/delta + cells exhibit a growth pattern different from that of conventional TcR alpha/beta + cells as they adhere promptly to surfaces and undergo morphological changes which can be summarized as follows: cells spread on the surface, form a distinct uropod and, in the final phase of adherence, emit long filopodia ending with adhesion plaques. Immunofluorescence studies of TcR gamma/delta + clones demonstrated the presence of submembraneous actin microfilaments and actin-binding protein confirming that these cells are capable of active motility which is related to the propensity of TcR gamma/delta + cells to home to epithelia. Scanning electron microscope analyses of effector/target cell conjugates showed that in TcR gamma/delta + cells the region of the uropodia next to the cell body is responsible for the binding to tumor target cells. Interestingly, immunofluorescence analyses revealed that LFA-1 molecules are predominantly distributed in the uropodium whereas they are virtually absent in the cell bodies. These morphological characteristics of TcR gamma/delta + cells may pertain to defensive mechanisms the mucosal level.