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The effectiveness of the Viratype Omniprobe in situ human papillomavirus tissue hybridization kit (Digene Diagnostics) was evaluated for the detection of HPV DNA in common orofacial lesions. Seventy mucocutaneous lesions were hybridized with a biotinylated Omniprobe that was specific for HPV types 6, 11, 16, 18, 31, 33, 35, 42, 43, 44, 45, 51, 52, and 56. Eighteen (25.7%) of the specimens analyzed had intranuclear positive signals for HPV. Probing with HPV 6/11, 16/18, and 31/33/35 to delimit the HPV genotype yielded HPV DNA 6/11 in 16 (88.9%) of the Omniprobe-positive specimens. Only squamous papilloma and condyloma acuminatum were found to harbor HPV DNA. Sites most frequently infected were the labial and buccal mucosa (21.7%) and the floor of the mouth (17.4%). These results suggest that hybridization with the Omniprobe provides appropriate sensitivity and specificity for detecting HPV in some benign proliferations of the oral cavity. However, the detection of HPV in oral squamous cell carcinoma, lichen planus, and keratoacanthoma remains problematic until more sensitive and specific molecular techniques are used.