1. Flufenamic and tolfenamic acids have recently been shown to inhibit receptor-mediated calcium influx in human neutrophils. The present work was designed to study the effects of these two nonsteroidal anti-inflammatory drugs on human peripheral blood lymphocyte activation. 2. Peripheral blood mononuclear cells (PBMNCs; containing 90% lymphocytes) were stimulated by mitogen concanavalin A (Con A) or by a combination of an inhibitor of microsomal Ca(2+)-adenosine triphosphatase thapsigargin (TG) and phorbol myristate acetate (PMA). The effects of the two fenamates on cell proliferation were compared with respective changes in calcium metabolism. 3. Flufenamic and tolfenamic acids (10-100 microM) inhibited both Con A and TG + PMA-induced [3H]-thymidine incorporation in a dose-dependent manner. At the same concentration range, the two fenamates inhibited the increase in intracellular free calcium concentration induced by Con A or TG + PMA. This effect was due to inhibition of calcium influx whereas calcium release from intracellular stores remained unaltered. 4. The inhibition of divalent cation influx was confirmed by showing that fenamates inhibited TG + PMA-induced Mn2+ influx. 5. The inhibitory effects of fenamates on PBMNC proliferation and Ca2+ influx were qualitatively similar with those of SK&F 96365, an earlier known inhibitor of receptor-mediated calcium entry. Ketoprofen, a chemically different prostaglandin synthetase inhibitor did not show similar suppressive effects on PBMNCs. 6. The data suggest that flufenamic and tolfenamic acids suppress proliferation of human peripheral blood lymphocytes by a mechanism which involves inhibition of Ca2+ influx and is not related to inhibition of prostanoid synthesis.