Rationale Previous studies by our group indicate that IL-2 can induce steroid resistance in T-cells. The purpose of this work was to investigate the role of IL-15, a cytokine with similar actions to IL-2, in the development of steroid unresponsiveness. Methods Peripheral blood mononuclear cells (PBMC) from healthy donors were grown in the presence and absence of IL-15 (100ng/ml) for 48h. Glucocorticoid receptor (GCR) alpha localization in response to dexamethasone (DEX) (10-6M) was assessed by fluorescence microscopy in CD19+ cells and analyzed by Slidebook ™ software. Results Incubation of unfractionated PBMC with IL-15 for 48h resulted in inhibition of GCRalpha nuclear translocation in response to 2h of DEX treatment in B cells but not non-B cells (CD19-) (P<0.0001, n=4). Pure B-cells incubated with IL-15 responded normally to steroids, but failed to translocate GCRalpha when they were grown in the presence of CD19- cells (P<0.0001). In order to further investigate the role of CD19- cells in the induction of B-cell unresponsiveness to steroids by IL-15, B cells were grown in cell culture membrane insert wells in the presence of autologous pure CD3+ (T-cells), CD14+ (monocytes) or CD56+ (NK cells). Co-culture of B-cells with NK cells and IL-15 resulted in failure of B-cells to translocate their GCR in response to DEX (P<0.0001). In contrast, B-cells cultured with T-cells or monocytes responded normally to steroids (P<0.0001). Conclusions B-cells develop unresponsiveness to steroids in the presence of NK cells after IL-15 stimulation.