Priming of neutrophil (PMN) oxidative responses is an integral component of host defense and inflammation and may contribute to cell‐mediated tissue injury. The characteristics and mechanisms of interferon‐ γ (EFN‐γ)‐induced oxidative priming of PMNs were explored in vitro. Following pretreatment of human PMNs with recombinant IFN‐γ, superoxide anion release was selectively primed toward the receptor‐initiated stimulants f‐Met‐Leu‐Phe (fMLP) and C5a but not toward the transduction‐mediated stimulants phorbol myristate acetate and A23187, a calcium ionophore. IFN‐γ also induced priming toward the stimulant NaF, a direct activator of guanine nucleotide regulatory proteins. Priming was not associated with changes in fMLP surface receptor expression or degranulation. Priming was dependent on de novo mRNA and protein synthesis. The immuno‐ regulatory lymphokine IFN‐y primes PMN oxidative responses, apparently via production of proteins that are involved in the early postreceptor transductional pathways of oxidative metabolism.