The separate and combined effects of transforming growth factor-β1 (TGF-β1) and prostaglandin E2 on human natural killer (NK) activity were studied. Peripheral blood lymphocytes (PBL) and large granular lymphocytes (LGL, 70–90% purity) were used as effector cells and K562 as targets. Overnight incubation of the effector cells with TGF-β1 resulted in a significant inhibition of NK activity. TGF-β1 did not influence the expression of CD3, CD 16, CD 18 or CD56 antigens on PBL. Combination of TGF-βl with indomethacin gave the same NK-suppressive effect as TGE-β1 alone, showing that the inhibition of NK acuvity by TGF-β1 is not due to an increase in PGE2 levels. TGF-β did not influence cAMP level in PBL whereas PGE2 significantly increased it. On the other hand. TGE-β1 and PGE2 showed an additive inhibitory effect on NK activity. TGF-β1 did not reduce the binding of PBL and LGL to K562. PGE2 suppressed the binding and TGF-β1 did not influence this suppression. TGF-β1 also suppressed IL-2-induced activation of NK activity and increase of expression of the granule proteins granzyme A and perforin. PGE2 did not appear to affect granzyme A and perforin contents. The results indicate that TGF-β1 and PGE2 suppress NK activity by different mechanisms.