We recently demonstrated a codominant role of C5aR and FcγRIII in the initiation of IgG immune complex-mediated inflammation in mice. In this study, we investigated the relative contribution of FcγRIII in the generation of several cytokines during experimental hypersensitivity pneumonitis/alveolitis in vivo. Induction of immune complex-alveolitis in C57BL/6 mice resulted in strong accumulation of neutrophils into the lung and enhanced chemotactic activity within bronchoalveolar lavage fluid accompanied by an increased production of the proinflammatory cytokines TNF-α and IL-1β as well as the ELR-CXC chemokines macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC). FcγRIII-deficient C57BL/6 mice (FcγRIII−/−) showed a marked reduction of the inflammatory response due to decreased production of TNF-α, IL-1β, and MIP-2. Results obtained in C57BL/6 mice either lacking the TNF-α class I receptor (TNF-αRI−/−) or treated with neutralizing anti-TNF-α mAb demonstrated an essential contribution of TNF-α for mediating IL-1β release, neutrophil influx, and hemorrhage. Surprisingly, MIP-2 and KC chemokine levels remained largely unaffected in TNF-αRI−/− mice or after functional inhibition of TNF-α. These data suggest that in immune complex alveolitis, the activation of FcγRIII may induce divergent downstream effector pathways with TNF-α acting independently of CXC chemokines to trigger the inflammatory response in C57BL/6 mice.