Successful therapy of tumors with lymphokine-activated killer (LAK) cells is presumably dependent on their cytolytic potential and their gaining access to the target cells through the microcirculation. The latter process involves dissemination through the microvessels, adhesion to the venular walls, and extravasation through them, all of which depend on the size and deformability of these effector cells. The aim of the present study was to measure the deformability of these cells quantitatively using a micropipet aspiration technique and to analyze the deformation data using a mathematical model which yielded parameters indicative of the rigidity of the cell membrane and the cytoplasm. Adherent rat LAK cells, consisting of a highly purified population of interleukin 2-activated large granular lymphocytes, with high cytotoxicity were obtained by a recently developed method. The deformability characteristics of fresh large granular lymphocytes (mean diameter, 7.2 microns), LAK cells (11.0 microns), fresh T-cells (6.6 microns), and concanavalin A-activated T-cells (9.7 microns) were compared. LAK cells were significantly less deformable than other cell types [about one-half at an aspiration pressure of -25 mm of H2O (P less than 0.001)]. Cell deformability was independent of cell size and calcium content of the medium. Analysis of the data with the mathematical model suggested that both the cell membrane and the cytoplasmic factors contributed to the rigidity of LAK cells. This increased rigidity coupled with their large cell size may explain high retention of LAK cells in the lungs immediately after i.v. injection and a reduction in tumor targeting due to external radiation. Finally, these results suggest that LAK cell therapy might be enhanced by intraarterial injection into an organ infiltrated by tumor metastases.