Forty-four men with penile intraepithelial neoplasia (PIN) and a matched control group of 88 men with condyloma acuminatum were evaluated in three centers studying anogenital human papillomavirus (HPV) infections. PIN and condyloma groups could not be distinguished on the basis of historical features or clinical presentation. Although PINs were more likely than condylomata to be pigmented (31/46 [67%] vs. 33/97 [34%], P < .001), 43% of PIN III were not pigmented, suggesting that pigmentation is not a sensitive indicator of high-grade PIN. HPV-16 infection, as determined by in situ hybridization, was closely associated with PIN III (0/24 PIN I contained HPV-16 vs. 12/13 PIN III, P < .001). Southern blot analysis demonstrated only episomal viral genomes, suggesting that integration is not an early event in penile neoplasia.