Types IIA and V secretory phospholipase A₂ (sPLA₂) are structurally related to each other and their genes are tightly linked to the same chromosome locus. An emerging body of evidence suggests that sPLA₂‐IIA plays an augmentative role in long‐term prostaglandin (PG) generation in cells activated by proinflammatory stimuli; however, the mechanism underlying the functional regulation of sPLA₂‐V remains largely unknown. Here we show that sPLA₂‐V is more widely expressed than sPLA₂‐IIA in the mouse, in which its expression is elevated by proinflammatory stimuli such as lipopolysaccharide. In contrast, proinflammatory stimuli induced sPLA₂‐IIA in marked preference to sPLA₂‐V in the rat. Cotransfection of sPLA₂‐V with cyclooxygenase (COX)‐2, but not with COX‐1, into human embryonic kidney 293 cells dramatically increased the interleukin‐1‐dependent PGE₂ generation occurring over a 24 h of culture period. Rat mastocytoma RBL‐2H3 cells overexpressing sPLA₂‐V exhibited increased IgE‐dependent PGD₂ generation and accelerated β‐hexosaminidase exocytosis. These results suggest that sPLA₂‐V acts as a regulator of inflammation‐associated cellular responses. This possible compensation of sPLA₂‐V for sPLA₂‐IIA in many, if not all, tissues may also explain why some mouse strains with natural disruption of the sPLA₂‐IIA gene exhibit few abnormalities during their life‐spans.