TCR alpha beta(+)/CD4(+) T-large granular lymphocyte (LGL) lymphocytosis is a subgroup of monoclonal T-LGL lymphoproliferative disorders that are different from the CD8(+) TCR alpha beta T-LGL. An increasing evidence supports the involvement of a common antigen-driven mechanism in the etiology of TCR alpha beta(+)/CD4(+) T-LGL. In this study, we tested several polymorphic markers associated with chronic viral infections and autoimmune diseases, including cytotoxic T-lymphocyte antigen-4 (CTLA-4), tumor necrosis factor-alpha (TNF-alpha), interteukin-10 (IL-10), interferon-gamma (IFN-gamma), RANTES, IL-1 alpha, FAS, FAS-ligand (FASL), and NKG2D, to investigate the potential association of these immunogenetic factors with the development of T-LGL. Overall, 38 patients with CD4(+) T-LGL were analyzed and compared with a group of both CD8(+)/TCR alpha beta(+) T-LGL patients (n = 43) and a group of control subjects (n = 176). Our results did not show any clear association between the different single nucleotide polymorphisms (SNPs) analyzed and the development of CD4(+)/TCR alpha beta T-LGL. An increase in the frequency of -380 (AA/GA) TNF-alpha genotype associated with a greater production of this cytokine was found among CD8+ T LGL patients in comparison to the CD4(+)LGL patients and the control. group. Our results suggest that the frequency of SNP of the genes coding for the studied immunoregulatory molecules are not associated with the development of CD4(+)/TCR alpha beta(+) T-LGL. (C) 2008 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.