Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by the expansion of phosphatidylinositol glycan class A (PIG-A) defective haematopoietic cells, probably due to the immune-mediated alterations of the bone marrow environment selecting PIG-A- stem cells. The present study investigated the presence of alterations of the immune system in a population of 11 PNH patients. The production of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), evaluated by intracellular cytokine analysis, and the frequencies of class I and II human leucocyte antigen (HLA) alleles were studied in comparison with healthy human subjects. Similar percentages of lymphocytes produced cytokines in PNH patients and controls after costimulation-independent activation; however, a negative correlation was found between the percentage of IFN-gamma producing cells and white cell or platelets counts. PNH patients showed an higher percentage, compared with controls, of IFN-gamma producing cells after costimulation-dependent activation. The frequency of HLA-A31 was higher in patients than in controls (27.2% vs. 4%), similarly to that of HLA-B7 (27.2% vs. 6%). With regard to class II alleles, 18% of PNH patients expressed DQB1*04 compared with none of 50 control cases. This study supports the hypothesis that immune alteration are present in PNH and that the immunogenetic background could influence the development of the disease.