The effect of promethazine on the metabolic responsiveness of human polymorphonuclear leukocytes to opsonized zymosan was evaluated by chemiluminescence (CL) assay under the following situations: (1) preincubation of granulocytes with promethazine; (2) simultaneous addition of zymosan and promethazine, and (3) addition of promethazine after initiation of phagocytosis and CL. The presence of promethazine inhibited light emission in all cases. The data suggest that promethazine interferes with the generation and/or subsequent activity of those reactive forms of oxygen which contribute to CL.