Organisms belonging to the Mycobacterium avium complex (MAC) are associated with life-threatening bacteremia in patients with the acquired immunodeficiency syndrome (AIDS). As these organisms survive within macrophages, we examined the ability of recombinant human granulocyte-monocyte colony-stimulating factor (GM-CSF) to activate human monocyte-derived macrophages to inhibit the intracellular growth or kill the most mouse-virulent MAC strain in our collection that belongs to serotype 1. While unstimulated cells did not inhibit intracellular growth of MAC, macrophages activated by GM-CSF (10-10(4) U/ml) inhibited or killed up to 58 +/- 5% of the initial inoculum. This activation was dose-dependent, with maximal change occurring with a dose of 100 U/ml after 72 hr exposure. Inhibition or killing was demonstrated if GM-CSF was given both before or after establishment of infection. The combination of GM-CSF (10(2) U/ml) plus TNF (10(2) U/ml) augmented macrophage killing (range, 31 +/- 4%) compared with GM-CSF (10(2) U/ml) alone, but the combination of recombinant human interferon-gamma (IFN gamma) plus GM-CSF resulted in a significant decrease in intracellular inhibition of growth or killing (13.3 +/- 2%) compared with 57.7 +/- 5% obtained with GM-CSF alone. These results indicate that: 1) GM-CSF can activate macrophages to inhibit intracellular growth or kill MAC; 2) killing may be augmented by TNF; and 3) IFN gamma may impair GM-CSF-dependent macrophage activation.