Aims and background Elevated TGF-β1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. However, the molecular mechanism of immunosuppression by TGF-β1 is not yet clarified. Methods IL-2-activated human NK cells were cultured with TGF-β1. Protein levels of NKG2D and DAP10 were examined by FACS or immunoblot analyses. Real-time RT-PCR was performed to quantify the transcription levels. MAPK inhibitors were used to investigate intracellular signaling. Results TGF-β1 down-regulated total and surface NKG2D, which was partially dependent on transcriptional regulation. TGF-β1 treatment of human NK cells resulted in significant changes in both transcriptional and translational levels of DAP10. Moreover, treatment with bafilomycin A1 or folimycin restored total NKG2D levels in TGF-β1-treated NK cells. The impaired NKG2D down-modulation by TGF-β1 was not associated with activation of the MAPK signaling pathway. Conclusions TGF-β1 down-modulates surface NKG2D expression by controlling the transcriptional and translational levels of DAP10.