We examined the ability of peripheral mononuclear cells (MNC) from patients with systemic lupus erythematosus (SLE) to produce γ‐interferon (γ‐IFN) in vitro. MNC from patients with SLE produced varying amounts of γ‐IFN upon mitogenic stimulation. However, they produced distinctly decreased amounts of γ‐IFN upon in vitro stimulation with interleukin‐2 (IL‐2). Deficient production seemed to be primary, rather than secondary to either excessive monocytic suppresion or failure of IL‐2 to bind to the MNC surface membranes. γ‐IFN‐specific RNA transcription, as determined by slot‐blot analysis, was severely decreased in MNC that had been stimulated with phytohemag‐glutinin or IL‐2. These findings suggest that MNC of patients with SLE have defects in the IL‐2 signal transduction which is required for production of γ‐IFN.