We examined the ability of peripheral mononuclear cells (MNC) from patients with systemic lupus erythematosus (SLE) to produce gamma-interferon (gamma-IFN) in vitro. MNC from patients with SLE produced varying amounts of gamma-IFN upon mitogenic stimulation. However, they produced distinctly decreased amounts of gamma-IFN upon in vitro stimulation with interleukin-2 (IL-2). Deficient production seemed to be primary, rather than secondary to either excessive monocytic suppression or failure of IL-2 to bind to the MNC surface membranes. gamma-IFN-specific RNA transcription, as determined by slot-blot analysis, was severely decreased in MNC that had been stimulated with phytohemagglutinin 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 gamma-IFN.