Background. The mucosal immune system balances the need of co-existing with commensal flora and food antigens while responding to pathogens. Inflammatory bowel disease (IBD), comprising Crohn disease (CD) and ulcerative colitis (UC), is a chronic inflam- matory condition of the gastrointestinal tract characterized by dysregulated innate and adaptive responses against commen- sal flora. The lectin-like NKG2D receptor is constitutively expressed on human NK cells, TCR , Natural Killer T (NKT, co-expressing the CD56 NK cell marker) and “clas- sical” CD8+ T cells and its expression can be positively or negatively regulated by cytokines and by chronic contact with its ligands. NKG2D engagement by its ligands triggers or potentiates lymphocyte cytotoxic activity and proinflamma- tory cytokine production. Human NKG2D ligands (MIC-A, MIC-B and the ULBP 1-4 family) are physiologically found only on mucosal and thymic epithelia in homeostatic con- ditions, but can be induced on several histotypes by stress factors as infections, neoplastic transformation and genotoxic damage. Inappropriate NKG2D-mediated lymphocyte activation, upon aberrant expression of NKG2D ligands, has been causally linked to autoimmune diseases such as rheumatoid arthritis, diabetes mellitus and celiac disease. Methods and aim. The aim of this study is to find whether alterations of the NKG2D/ligands pathway may play a role in pathogenetic mechanism leading to chronic inflammation in IBD paediatric patients. We analyzed peripheral blood monu- clear cells of 18 CD pts: 10 (with active disease, PCDAI score 10), and 8 in remission (PCDAI score 10), and 5 in remission (PUCAI score 10) and 26 age-matched non-IBD controls for the expression of NKG2D receptor, MIC-A and MIC-B molecules, by immuno-staining and FACS analysis. Results. The immunocytofluorimetric analysis of NKG2D receptor in distinct PBMC subset shows a significa- tive increase of the receptor in several T cell subpopulations, such as / TCR and NKT cells in IBD patients, as com- pared to age-matched controls. The augmented expression is selectively present in patients affected by UC (p 0.05 vs controls), while it is not shown in CD; moreover, the augmentation of NKG2D expression correlates with the activity of the disease (p 0.01 for / T cells, and p 0.05 for NK/T cells). Interestingly, constitutive expression of NKG2D on “classical” CD8+ T lymphocytes does not seem to be affected, and no induction is observed on CD4+ T lymphocytes, at variance with recent published data on adult IBD patients (Allez et al., 2007). We also assessed the expression of MIC-A/B ligands on lymphomononuclear cells. MIC-A/B expression was induced on a proportion of patients’ lymphocytes, where the induc- tion is more abundant on CD patients (p 0.05 vs controls) and correlates with the remission status (p 0.05 vs controls). Interestingly, NKG2D ligands are also induced on circulat- ing monocytes in IBD patients vs controls (p 0.05), where the induction is more pronounced in patients with the active disease (p 0.05 vs controls), and it is comparably observed both in CD and UC. Alterations in NKG2D/ligands expression pattern are also shown in patients’ mucosal samples. Conclusion. The results of this study provide a first evidence of a dysregulation in the expression of the immunoreceptor NKG2D and of its main ligands on selected mononuclear cell subsets in the peripheral blood of IBD paediatric patients. Interestingly, NKG2D expression in the periphery is augmented on innate-like T lymphocyte subpop- ulations (/ TCR, NKT), while “classical” T cell subsets (CD4+ and CD8+) display a normal phenotype; on the other hand, the induction of MIC-A/B ligands shows a distinct pattern on lymphocytes and on monocytes.