The transfusion of incompatible red cells may result in fever and systemic symptoms. The mechanisms by which these symptoms are produced in the setting of antibodies that do not usually fix complement, as in the Rh system, are obscure. It has been hypothesized, on the basis of their known biologic activities, that a specific set of cytokines may be involved in such transfusion reactions. Therefore, the production of the inflammatory cytokines interleukin‐1 beta (IL‐1 beta), tumor necrosis factor (TNF), interleukin‐6 (IL‐6), and interleukin‐8 (IL‐8) by human monocytes in response to red cells sensitized with anti‐D was investigated, as a model of IgG‐dependent hemolytic transfusion reactions. IL‐1 beta, IL‐6, and IL‐8 were detectable in the culture supernatants at 4 to 6 hours and increased up to 24 hours, whereas TNF peaked at 6 hours. Immunocytochemical stains of cell preparations demonstrated IL‐1 beta, IL‐8, and TNF in monocytes engaged in erythrophagocytosis. IL‐8 production and phagocytosis could be inhibited by monomeric IgG, but Fab fragments of a monoclonal antibody specific for the low‐affinity IgG receptor Fc gamma RII could not be, which suggests the involvement of the high‐affinity receptor Fc gamma RI. Neutralizing antisera to IL‐1 beta and TNF did not abrogate the production of IL‐8, which suggests that sensitized red cells serve as a primary signal for this cytokine. These findings indicate that the production of inflammatory cytokines by phagocytes may be responsible for the symptomatology of IgG‐mediated hemolytic transfusion reactions.