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Histopathologic diagnosis of cervical biopsies determines clinical management of patients with an abnormal cervical cancer-screening test yet is prone to poor interobserver reproducibility. Immunohistochemical staining for biomarkers related to the different stages of cervical carcinogenesis may provide objective standards to reduce diagnostic variability of cervical biopsy evaluations but systematic, rigorous evaluations of their potential clinical utility are lacking. To address diagnostic utility of human papillomavirus (HPV) L1, p16(INK4a), and Ki-67 immunohistochemical staining for improving diagnostic accuracy, we conducted a community-based and population-based evaluation using 1455 consecutive cervical biopsies submitted to the Department of Pathology at the University of Virginia during a period of 14 months. Thin-sections of each biopsy from 1451 of 1455 (99.7%) biopsies underwent evaluation of immunohistochemical stains for the 3 biomarkers, masked to the original diagnosis, and the results were compared with an adjudicated, consensus diagnosis by 3 pathologists. p16 immunostaining, using the strongest staining as the cutpoint, was 86.7% sensitive and 82.8% specific for cervical intraepithelial neoplasia (CIN) grade 2 or more severe (CIN2(+)) diagnoses. The performance of p16(INK4a) was more sensitive (P<0.001), less specific (P<0.001), and of similar overall accuracy for CIN2(+) compared with the combined performance of all pathologist reviews in routine clinical diagnostic service (sensitivity=68.9%, specificity=97.2%). Ki-67 immunostaining was also strongly associated with a CIN2(+) diagnosis but its performance at all staining intensities was inferior to p16 immunostaining, and did not increase the accuracy of CIN2(+) diagnosis when combined with p16(INK4a) immunostaining compared with p16(INK4a) immunostaining alone. We found no utility for L1 immunostaining in distinguishing between CIN and non-CIN. In conclusion, with a rigorous evaluation, we found immunohistochemical staining for p16 to be a useful and reliable diagnostic adjunct for distinguishing biopsies with and without CIN2(+).