This study demonstrates a synergistic effect of IFNγ and PMA on superoxide generation by human monocytes. A strict correlation was observed between the induction of superoxide production and PK-C activation by PMA alone. No such correlation was evident for IFNγ. However, exposure of the cells to IFNγ for 10 to 15 hr prior to PMA treatment enhanced both superoxide production and PK-C activation. Using protein kinase inhibitors, we noticed that while PMA exerted its effect by activating PK-C, IFNγ operated via activation of calcium/calmodulin-dependent or some other calcium-dependent protein kinases. These kinases appeared to be involved in the effect of IFNγ on superoxide production, as well as in its potentiation of PMA activity.