Several studies have shown statistical evidence of association between nasopharyngeal carcinoma (NPC) and specific human leukocyte antigen (HLA) alleles and highlighted the presence of candidate genes for this cancer within or nearby the HLA. Given their chromosomal location within HLA and their determining role in the immune response to tumor cells, we designed a case-controlled study to investigate the potential association of the genetic variation of the tumor necrosis factor-alpha (TNF-alpha) and that of the heat shock protein 70-2 (HSP70-2) with NPC. We used the polymerase chain reaction and restriction enzyme digestion to characterize the variation of the TNF-alpha promoter region and that of the HSP70-2 gene in 140 Tunisian patients with primary NPC and 274 healthy control subjects. No association was found between genetic variations in TNF-alpha and the risk of NPC in Tunisians. In contrast, a significant relative risk of NPC was found associated with the HSP70-2 homozygous genotype (P2/P2) (OR=2.309; P=0.006). The P2/P2 genotype of the HSP70-2 gene may be a marker of increased risk of NPC in Tunisians.