We report here that the 12‐lipoxygenase metabolite of arachidonic acid, 12‐hydroxy‐5Z, 8Z, 10E, 14Z, eicosatetraenoic acid (12‐HETE), stimulates cAMP production in human fibroblasts among various cultured cell lines tested. Although 12‐HETE seemed to stimulate the phospholipase C (PLC)‐protein kinase C (PKC) system, inhibitors against PLC and PKC did not reduce the cAMP production induced by 12‐HETE, indicating that the activation of PLC‐PKC system is not positively coupled with the stimulation of cAMP production. On the other hand, the cAMP production induced by 12‐HETE was dependent on the Ca²⁺/calmodulin system in the cells. The results suggest that 12‐HETE specifically stimulates Ca²⁺/calmodulin‐dependent adenylyl cyclase to increase cAMP level in the fibroblasts. J Cell Physiol 178:63–68, 1999. © 1999 Wiley‐Liss, Inc.