The stimulation of granulocyte O2- production by concanavalin-A can be reversed with alpha-methylmannoside. Such cells can be reactivated to generate O2- by adding phorbol myristate acetate or N-formyl-methionyl- leucyl-phenylalanine. Opsonized zymosan, however, is not an effective stimulant to these cells. alpha-Methylmannoside prevents, but does not reverse, depolarization of granulocytes by concanavalin-A. Previously activated cells have a shorter lag time for reactivation by phorbol myristate acetate. Incubation in 2-deoxyglucose of cells previously treated with concanavalin-A and alpha-methylmannoside prevents reactivation. EGTA prevents concanavalin-A-stimulated O2- production only when added prior to the stimulant. EGTA has only a slight effect on reactivation. alpha-Methylmannoside prevents concanavalin-A- stimulated release of lysozyme only when added prior to the stimulant. Prior treatment of cells with concanavalin-A and alpha-methylmannoside inhibits subsequent ingestion of complement-coated particles. We conclude that although the O2--generating system can be reversibly activated with concanavalin-A followed by alpha-methylmannoside, these cells are different from untreated cells. Cells treated in such a way do not respond to all stimuli, remain depolarized, have shortened lag times, no longer require calcium for activation, continue to degranulate, and do not ingest well. Thus, although some changes that accompany the interaction of stimuli with granulocytes are reversible, some are not, and the previously activated cell does not return to a true resting state.