Persistent human papillomavirus infections cause infected epithelial cells to lose cellular polarity leading to cell transformation. Glycolipid-enriched membrane (GEM) rafts are implicated in polarized sorting of apical membrane proteins in epithelial cells and even in signal transduction. The MAL and BENE are essential component of the GEM raft's machinery for apical sorting of membrane proteins. In this study we demonstrated down-regulation of MAL and BENE mRNA in over two-thirds of primary cervical squamous cell cancers (14 and 15 of 20 cases, for MAL and BENE, respectively) when compared to corresponding non-cancerous uterine squamous cells. Allelic loss or hyper-methylation was not accompanied by MAL or BENE mRNA down-expression in human primary cervical cancers in microsatellite allelic analysis and HpaII-PCR-based methylation analysis of the MAL and BENE genomic region. In addition, we note down-regulation of these genes in established cervical cancer cell lines. These results suggest that down-regulation of MAL and BENE genes, which are essential components of the cellular polarized sorting system, play an important role in human cervical squamous cell cancer development.