Identification of human papillomavirus (HPV)-related early cervical neoplasia and its distinction from benign epithelial alterations is based on either subjectively applied morphologic criteria or on identification of associated papillomaviruses. The direct and indirect consequences of HPV infection, however, potentially include upregulation of some host genes. We investigated one candidate, cyclin E, as a possible marker for HPV-related early squamous lesions. Serial paraffin sections from 92 archival cervical biopsy specimens were analyzed, including 19 non-neoplastic biopsy specimens, 30 low-grade and 31 high-grade squamous intraepithelial lesions (SILs), and 12 invasive carcinomas. Four parameters (histologic diagnosis, cyclin E staining, HPV status and, in selected cases, Ki-67 staining) were scored, and their relationship(s) were evaluated by the chi2 independence test. Twenty-one, 73, 79, and 75% of nonlesional epithelia, low-grade SILs, high-grade SILs, and invasive squamous cell carcinomas, respectively, were HPV positive (P < .001 for HPV status vs. diagnosis). Cyclin E staining was nuclear in distribution, and the frequency of positive staining, ie., moderate or strong intensity, was significantly higher (P < .001 for cyclin E staining vs. diagnosis) in all of the lesional epithelia (92.3, 51.6, and 50% of low-grade and high-grade SILs and carcinomas, respectively) compared with nonlesional epithelium (5.9%). Cyclin E positivity and/or HPV positivity was seen in 100% of the low-grade SILs. Epithelial Ki-67 and cyclin E staining were strikingly different in frequency and distribution. Cyclin E was undetectable in basal cells of normal mucosa (which were positive for Ki-67) and limited to suprabasal epithelium in noninvasive lesions. Cyclin E expression correlates strongly with morphologic features of HPV-related preinvasive and invasive cervical disease. This correlation is most pronounced in low-grade SILs. The possibility that in vivo cyclin E staining is a generic marker for HPV infection in low-grade SILs merits additional study.