The histopathologic diagnosis of vulvar condyloma acuminatum is often based on architectural features that are not specific for human papillomavirus (HPV) infection. Because HPV-associated lesions show increased cellular proliferation, the authors evaluated the usefulness of MIB-1 immunostaining as an aid in the differential diagnosis of cases equivocal for condyloma. The MIB-1 immunostaining pattern was correlated with HPV DNA detection in condyloma acuminatum (CON-A; n = 15), "consistent with condyloma" (c/w CON-A; n = 26), fibroepithelial polyp (FEP; n = 14), and squamous papilloma (n = 10). HPV was detected in 100% of the CON-A cases, and all cases demonstrated MIB-1-positive nuclei in the upper two thirds of the epithelial thickness. With this definition of MIB-1 positivity, there was complete concordance between MIB-1 positivity and HPV detection for all cases (kappa = 0.88). Of the cases c/w CON-A, 17 of 26 (65%) were positive for both MIB-1 and HPV, and could be reclassified as CON-A, whereas 35% were identified as an overdiagnosis based on negative results. In addition, two cases of FEP were MIB-1 and HPV positive, and thus were identified as an underdiagnosis. These results suggest significant overdiagnosis of cases equivocal for condyloma, and indicate that MIB-1 immunostaining is a beneficial adjunctive test when the morphologic features are suggestive but not diagnostic for CON-A.