Downregulation of HLA class I expression is a common event in tumor biology. Various underlying mechanisms have been defined in different tumors, but the knowledge of HLA loss mechanisms in cervical carcinoma is limited. To identify causalities for loss of surface expression, we performed a detailed investigation of HLA class I phenotypes and genotypes in 5 primary cervical tumors and on derivative cell lines. Protein expression on primary tissues and cell lines was evaluated by immunohistochemistry and flow cytometry respectively, using a broad panel of allele-specific monoclonal antibodies. Loss of expression was seen in 3 cases, comprising B15-locus loss, B15-allelic loss, and loss of an A74/B15 haplotype and an A24 allele of the other haplotype. Cytokine treatment induced re-expression of the B15-locus loss, suggesting a regulatory defect underlying lack of constitutive expression in this tumor. In contrast, molecular analyses at the DNA and/or RNA level showed that the other, non-inducible, losses were associated with chromosomal HLA gene defects. Loss of heterozygosity analysis was performed to confirm larger genomic deletions. This study shows that HLA gene defects by mutation or loss of heterozygosity as well as regulatory defects are involved in cervical carcinogenesis. The resulting changes in HLA expression may directly affect the efficacy of the immune response to these human papillomavirus-related neoplasms. Heterogeneity in the underlying loss mechanisms may offer individual tumors various opportunities to escape immune surveillance, and may severely compromise T-cell based therapy.