To inform the proposed systematic adjudicative staining of cervical intraepithelial neoplasia grade 2 (CIN2) and equivocal diagnoses, we characterized diagnostic heterogeneity across 15 laboratories. Laboratory-specific distributions of 37,486 biopsy specimen diagnoses were compared after adjusting for preceding cytology. In a subset of preceding cytology specimens, HPV16 genotyping was considered an indicator of lesion severity. Distributions of normal and CIN1 diagnoses varied widely, with laboratories favoring either normal (5.5%-57.7%) or CIN1 diagnoses (23.3%-86.7%; P < .001 for normal:CIN1 variability). Excluding extreme values, 6.2% to 14.4% of diagnoses were CIN2 (P < .001). For CIN2 diagnoses, HPV16 positivity in the preceding cytology varied between 39.0% in the largest laboratory and 57.4% in others (P < .001), suggesting differential interpretation, not population differences, as a cause of variability. In conclusion, the frequency of diagnoses requiring special staining (p16(INK4a) immunostaining) to adjudicate equivocal CIN2 will be sizable and vary between laboratories, especially if extended to a fraction of CIN1 lesions.