We previously mapped a nonrandom frequent loss of heterozygosity (LOH) region in cervical cancers to 1 Mb of 6p23. Here, we describe the identification of a novel cervical cancer susceptibility gene, CD83. The gene was identified by several complementary approaches, including a family-based association study, comparison of transcript expression in normal and cancerous tissue, and genomic sequencing of candidate. CD83 encodes an inducible glycoprotein in the immunoglobulin superfamily and is a marker for mature dendritic cells. The association study that includes 377 family trios showed that five single nucleotide polymorphisms (SNP) within 8 kb of its 3'-end showed significant allelic association that was strengthened in a subgroup of women with invasive cancers infected by high-risk human papillomavirus type 16 and 18 (rs9296925, P = 0.0193; rs853360, P = 0.0035; rs9230, P = 0.0011; rs9370729, P = 0.0012; rs750749, P = 0.0133). Investigation of CD83 uncovered three alternative transcripts in cervical tissue and cell lines, with variant 3 (lacking exons 3 and 4) being more frequent in cervical cancer than in normal cervical epithelium (P = 0.0181). Genomic sequencing on 36 paired normal and cervical tumors revealed several somatic mutations and novel SNPs in the promoter, exons, and introns of CD83. LOH was confirmed in >90% of cervical cancer specimens. Immunofluorescence colocalized CD83 protein to the Golgi apparatus and cell membrane of cervical cancer cell lines. None of seven nearby genes was differentially expressed in cervical cancer. The importance of CD83 in epithelial versus dendritic cells needs to be determined, as does its role in promoting cervical cancer.