AbstractTo better understand the underlying pathways of cervical carcinogenesis, cDNA microarray analysis was performed on 2 sets of squamous cell carcinomas (SCCs) and their adjacent normal squamous epitheliums. Consistently altered expression was detected for 32 genes. Real‐time RT‐PCR analysis was conducted on a selected subset of these genes (S100A2, GPC4, p72, IGFBP‐5, TRIM2 and NAB2) for 14 additional SCCs and 10 normal epithelia. This found that, of the 6 candidate genes, only the insulin‐like growth factor binding protein‐5 (IGFBP‐5) mRNA was generally and significantly under‐expressed in SCCs (p < 0.001). All normal cervical epithelia (30 of 30) stained positively for IGFBP‐5 protein, with 70% showing strong staining, whereas 65% (17/26) of SCC had complete loss of IGFBP‐5, and only 8% (2/26) SCC retained strong expression (p < 0.001). Immunohistochemistry of premalignant cervical intraepithelial neoplasia (CIN) lesions shows a significantly weaker or negative staining in advanced CIN3 lesions compared with normal squamous epithelia (p = 0.001). This is the first study to show that down‐regulation of IGFBP‐5 protein correlates with cervical carcinogenesis and does so at a preneoplastic stage. © 2007 Wiley‐Liss, Inc.