Infection with oncogenic human papillomavirus (HPV) is considered to be the major etiologic event for cervical cancer. Tumor necrosis factor α (TNFα), a proinflammatory cytokine, may be involved in orchestrating an antitumor immune response against human papillomavirus expressing cervical cancer cells. Hence, loss of TNFα could be advantageous for tumor cells to escape immune clearance. The aim of our study was to investigate TNFα gene expression and epigenetic characteristics associated with the loss of TNFα expression in cervical cancer. To this end, we examined TNFα expression, loss of heterozygosity (LOH) at 6p21.3, the locus of TNFα, mutational status of the TNFα locus, loss of the TNFα promoter variant 2 allele and CpG hypermethylation of the TNFα promoter. RNA in situ hybridization showed absence of TNFα expression in 45% of 63 tumors. LOH occurred in 57% of the tumors and was not concordant with absence of TNFα mRNA. No mutations in the TNFα gene were identified in 15 cases deficient in TNFα expression exhibiting LOH. Furthermore, lack of TNFα expression did not correlate with promoter methylation. In conclusion, TNFα mRNA expression is absent in nearly half of the cervical tumors analyzed. Neither promoter methylation nor genetic causes for lack of expression were evident.