Neutrophils are effector cells of innate immune responses. Stimulated by interferon-gamma (IFN-gamma) to express HLA-DR, neutrophils acquire accessory cell functions for superantigen-mediated T cell activation. In vitro HLA-DR induction on neutrophils varies in a functionally relevant way as levels of MHC class II expression and magnitude of neutrophil induced T cell responses are correlated functions. The aim of this study was to assess whether IFN-gamma induces HLA-DR on human neutrophils in a donor dependent fashion in vivo and to define regulatory events operative in MHC class II expression of neutrophils. In vivo administration of rhIFN-gamma in 55 patients with renal cell carcinoma resulted in a varying increase of HLA-DR on neutrophils. By setting a cut-off for response at>10% HLA-DR positive neutrophils, HLA-DR responders (51%) were as frequent as nonresponders (49%). In vivo kinetic studies revealed a peak expression of HLA-DR on neutrophils 48 h after rhIFN-gamma application, while nonresponders remained HLA-DR negative over a 72-h period. In vitro IFN-gamma stimulated neutrophils recapitulated the response profiles observed in vivo. No differences in IFN-gamma dependent CD64 and invariant chain expression, and IFN-gamma serum levels were observed among the response subgroups. HLA-DR mRNA was detected in neutrophils from rhIFN-gamma treated responders and nonresponders, HLA-DR protein solely in lysates of responder neutrophils. IFN-gamma stimulated HLA-DR expression on neutrophils is subject to donor dependent variations in vivo, which result from rather post-transcriptional than transcriptional regulation. Due to their abundance in inflammatory reactions heterogeneous HLA-DR expression by neutrophils could determine the outcome of superantigen-driven diseases.