Antibody-antigen complexes initiate the inflammatory response and are central to the pathogenesis of tissue injury. The classical model for this immunopathological cascade, the Arthus reaction, was reinvestigated with a murine strain deficient in Fe receptor expression. Despite normal inflammatory responses to other stimuli, the inflammatory response to immune complexes was markedly attenuated. These results suggest that immune complex-triggered inflammation is initiated by cell bound Fe receptors and is then amplified by cellular mediators and activated complement. These results redefine the inflammatory cascade and may offer other approaches for the study and treatment of immunological injury.