The role of phospholipase A2 (PLA2) in tumor cell growth was investigated using SK-N-MC human neuroblastoma cells. 4-Bromophenacyl bromide (BPB) and mepacrine (Mep), known PLA2 inhibitors, suppressed growth of the tumor cells in a dose-dependent manner without a significant cytotoxicity. Melittin (Mel), a PLA2 activator, enhanced the cell growth in a concentration-dependent fashion. The growth-enhancing effects of Mel were significantly reversed by the co-treatment with PLA2 inhibitors. In addition, Mel induced intracellular Ca2⁢ release from internal stores like as did serum, a known intracellular Ca2⁢ agonist in the tumor cells. Intracellular Ca2⁢ release induced by these agonists was significantly blocked by PLA2 inhibitors at growth-inhibitory concentrations. Arachidonic acid (AA), a product of the PLA2-catalyzed reaction, induced cell growth enhancement and intracellular Ca2⁢ release. These effects of AA were significantly blocked by BAPTA/AM, an intracellular Ca2⁢ chelator. Taken together, these results suggest that the modulation of PLA2 activity may be one of the regulatory mechanisms of cell growth in human neuroblastoma cells. Intracellular Ca2⁢ may act as a key mediator in the PLA2-induced growth regulation.