We examined the effects of interferon‐γ (IFN‐γ) on 100% pure human mast cells generated in suspension cultures of umbilical cord blood mononuclear cells in the presence of stem cell factor (SCF) and interleukin‐6 (IL‐6). When mast cells were suspended in serum‐free medium without any cytokine after the withdrawal of SCF and IL‐6, they died over a period of 5 days because of apoptosis. IFN‐γ in the cultures suppressed apoptosis and prolonged their survival in a dose‐dependent manner. This survival‐promoting effect of IFN‐γ was blocked by neutralizing antibodies to IFN‐γ or to IFN‐γ receptor (IFN‐γR). When mast cells were incubated with IFN‐γ in serum‐free medium for more than 4 hr during sensitization, immunoglobulin E (IgE)/anti‐IgE antibody‐induced histamine release was effectively enhanced. Polymerase chain reaction (PCR) amplification of the α‐chain of IFN‐γR (IFN‐γRα) yielded products of the correct size predicted from the sequence of the receptor. In addition, flow cytometry using anti‐IFN‐γR monoclonal antibodies (mAbs) indicated that these mast cells bear IFN‐γR on their surface. These findings suggested that IFN‐γ activates human mast cells via specific receptors in certain aspects of inflammatory reactions.