The effect of colchicine on the uptake of oxygen by human leukocytes during phagocytosis of live streptococci or of killed staphylococci was compared with the effect of colchicine on phagocytosis per se, measured in a sensitive bacterial system. The increase in oxygen consumption that normally accompanies phagocytosis was consistently diminished in leukocytes incubated with colchicine in concentrations as low as 2.5 x 10(-6) mole per L (1 mug per ml), and this inhibition was dosage dependent. Yet there was no evidence of decreased phagocytosis with concentrations of colchicine as high as 2.5 x 10(-4) mole per L (100 mug per ml). Furthermore, with measurements at 20, 40, and 60 minutes, the rate of phagocytosis was comparable with and without colchicine.A clue to the dissociation between oxygen consumption and phagocytosis was found in rapidly dried preparations of the incubated leukocytes. Ingested bacteria were present in both control and colchicine-treated granulocytes. In addition, control cells showed normal loss of granules (lysosomal particles) and prominent cytoplasmic vacuoles (digestive vacuoles). Colchicine-treated cells, however, showed less such degranulation and vacuolization. Measurements of granule-associated acid phosphatase activity after phagocytosis support the morphologic observations of less degranulation in colchicine-treated leukocytes. The muted metabolic and morpholgic response to phagocytosis in colchicine-treated cells may be important for the anti-inflammatory effect of colchicine in acute gouty arthritis. Colchicine may also find wider use in defining structure-function dependencies in metabolically stimulated cells.