Rat mast cells express high-affinity receptors for IgE (Fc epsilon RI) and low-affinity receptors for IgG (Fc gamma R). In this study, the capacity of IgG to activate the rat basophilic leukemia (RBL-2H3) and rat peritoneal mast cells was investigated. Immune complexes formed with purified rat IgG and antigen as well as chemically cross-linked rat IgG induced histamine release from RBL-2H3 cells. This stimulation was inhibited by pre-incubation of the cells with saturating concentrations of monomeric IgE. With chemically cross-linked rat IgG of each subclass, only IgG2a stimulated histamine release from RBL-2H3 cells and this release was also inhibited by prior saturation of the Fc epsilon RI with monomeric IgE. Identical results were obtained with rat peritoneal mast cells. In binding experiments, IgE and cross-linked rat IgG2a bound to rat Fc epsilon RI transfected into CHO cells. Monomeric rat IgG2a, cross-linked rat IgG1, IgG2b, IgG2c and rabbit IgG did not bind to Fc epsilon RI. Stimulation of RBL-2H3 cells with aggregated IgG2a induced phosphorylation of tyrosines in the beta and gamma subunits of the Fc epsilon RI. Thus, although RBL-2H3 and rat peritoneal mast cells have Fc gamma R, the IgG-mediated stimulation of these cells for histamine release was by the Fc epsilon RI. Altogether, these data demonstrate that the rat Fc epsilon RI is a functional receptor with low affinity for rat IgG2a.