In an earlier study, we reported IgE-containing circulating immune complexes (CICs) in 66.6% of the patients with rheumatoid arthritis who were studied, especially in those with extra-articular manifestations. The present study was undertaken to examine the possible role of these immune complexes in inflammatory cell activation. Twelve patients with classic or definite rheumatoid arthritis, two with primary Sjögren's syndrome, and three patients with systemic lupus erythematosus were studied. Of these 17 patients, 10 were IgE-containing CIC positive, and seven patients were IgE-containing CIC negative. Polyethylene glycol-precipitated IgE-containing CICs and IgG-containing CICs of these patients were coated on plastic wells and incubated with suspensions of neutrophils. As a parameter of cell activation, superoxide release (SOR) was measured by cytochrome C reduction in the supernatant after 30, 60, and 90 minutes. There was a significant SOR up to 38% of the zymosan control when IgE-containing CICs were incubated with neutrophils. Furthermore, there was a significant correlation between the level of IgE-containing CICs and the amount of SOR, but not between the level of IgG-containing CICs and the amount of SOR. These results suggest a possible role for IgE-containing CICs in the activation of inflammatory cells in connective tissue diseases.