Minichromosome maintenance and topoisomerase II alpha proteins play an important role in the regulation of eukaryotic DNA replication, and are overexpressed in a number of dysplastic and malignant tissues. ProExC antibody is a novel biomarker cocktail containing antibodies against topoisomerase II alpha and minichromosome maintenance 2 proteins. Our purpose was to evaluate the sensitivity, specificity, and predictive value of ProExC in dysplastic squamous and glandular lesions of the cervix. Nine low-grade squamous intraepithelial lesion, 35 high-grade squamous intraepithelial lesion, 23 squamous metaplasia, and 14 adenocarcinoma in situ specimens were retrieved from our hospital files. ProExC immunostaining was performed. ProExC had sensitivity, specificity, and positive and negative predictive value of 89%, 100%, 100%, and 82%, respectively, for distinguishing high-grade squamous intraepithelial lesion from squamous metaplasia, and 93%, 100%, 100%, and 98%, respectively, for distinguishing adenocarcinoma in situ from reactive benign endocervix. ProExC is a valuable marker for distinguishing dysplastic squamous and endocervical lesions of the cervix from squamous metaplasia in histologic sections. ProExC may eventually be used in conjunction with morphologic and human papillomavirus evaluation for better classification of indeterminate cervical lesions in Papanicolaou smears.