To evaluate immune cell activation in patients with melioidosis, serum samples were assayed for interferon-γ (IFN-γ), soluble interleukin-2 receptors (sIL-2R), and soluble CDS protein (sCDS). Forty patients with sepsis (23 fatal cases, 17 survivors) and 13 with localized disease were studied during acute illness; 12 additional patients were studied after discharge while on maintenance antimicrobial therapy. Serum concentrations of IFN-γ and sIL-2R were greatly elevated, but sCDS concentrations were not. These levels increased with disease severity and were associated with fatal outcomes. Macrophage activation by high concentrations of the cytokine IFN-γ may contribute to pathophysiology and death in septicemic patients. Both IFN-γ and sIL-2R seem to be predictive of outcome in patients with severe melioidosis and may prove useful in detection of relapse.