The objective of this study was to determine nitric oxide (NO) and superoxide anion release (O ₂ ⁻ ) by neutrophils (PMNs) in the septic multiple organ dysfunction syndrome (MODS) and to compare them with the response of normal cells to lipopolysaccharide (LPS) and cytokines. NO production was measured by the release of nitrites in the medium, its maximal production rate by a modified oxyhemoglobin assay and O ₂ ⁻ by standard methods. Normal cells were incubated with LPS, gamma interferon (IFN-γ), or tumor necrosis factor (TNF-α) alone or in combination. Results showed that PMN release of both NO and O ₂ ⁻ was reduced in septic samples; in contrast, an association of LPS, IFN-γ, and TNF-α promoted maximal NO release by normal cells (40–50%). We conclude that while interaction of normal PMNs with cytokines increases NO and O ₂ ⁻ release, progression of sepsis to a multiple organ dysfunction impairs these responses in both functions.