Natural killer (NK) activity is mediated by a small population of peripheral blood cells that exhibit the homogeneous morphology of large granular lymphocytes (LGL). In recent studies, human NK cell clones have been shown to contain a 200,000-Mr (relative molecular mass) protease-resistant chondroitin sulphate A proteoglycan, which has been localized to the secretory granule by X-ray dispersive analysis and by its resistance to cleavage by extracellular addition of chondroitinase AC or ABC (ref. 7). In the present study, we have used six different human NK cell clones to demonstrate that release of 35S-proteoglycan correlates closely with cytolytic activity against various NK cell targets. When NK activity is blocked by monoclonal antibodies at either the effector cell level (LFA-1) or at the target cell level (TNKTAR), there is a concomitant decrease in exocytosis of proteoglycan. Monoclonal antibodies directed against recognition structures, for example anti-NKTa and anti-T3 (ref. 10), function as soluble stimuli, capable of initiating the release of 35S-proteoglycan. Taken together, these results provide strong evidence for the stimulus-specific release of chondroitin sulphate A proteoglycans from NK cells when the cytolytic process is activated.