AbstractIn the previous studies, some human major histocompatibility complex (MHC) genes such as TNF, LTA and human leukocyte antigen (HLA)‐DR2 genes and A1‐B8‐TNF−308A haplotype were implied in non‐Hodgkin’s lymphoma (NHL) outcome. In the current study, we have assigned most probable six‐locus haplotypes determined by HLA‐A, ‐Cw, ‐B and ‐DRB1 highly polymorphic genes and non‐HLA LTA+252 and TNF−308 single nucleotide polymorphisms (SNPs) in 152 NHL Caucasian French patients. We have broadly mapped the MHC region by its component blocks and tagging alleles. Ten frequent (with haplotype frequency >1%) six‐locus extended haplotypes (EHs) were revealed in NHL patients. The only two adjacent locus fragment of 8.1 EH associated with shortened freedom from progression (FFP) was B*08‐LTA+252G (P= 0.0084, RR = 2.45). Interestingly, 305‐kbp‐long, four‐locus fragment of 8.1 EH, Cw*07‐B*08‐LTA+252G‐TNF−308A block was much strongly associated with shortened FFP (P= 0.00045, RR = 3.26). The analysis of further extended haploblocks comprising five or six loci showed weaker association with outcome measures, suggesting linkage disequilibrium to be the cause of DRB1*03 and A*01 allele associations. In contrast, all fragments of 7.1 EH influenced FFP favorably with top association of TNF−308G allele. In multivariate analysis, only Cw*07‐B*08‐LTA+252G‐TNF−308A and TNF−308G‐DRB1*01 haplotypes remained predictive for shortened FFP (P= 0.024 and 0.027, respectively) and independent of International Prognostic Index (P= 0.00044). This study reveals that the block composition of EHs may cause important functional differences for NHL outcomes. Further study will be required in NHL patients by fine mapping with dense microsatellite or SNP tags to define susceptibility genes in associating regions.