The role of human papillomavirus (HPV) in orthokeratinized odontogenic cysts (OOCs) has rarely been studied. The objective is to describe the clinicopathological findings in a series of OOCs from a Spanish population that were investigated in relation to the possible presence of HPV. Methods A clinicopathological retrospective analysis followed by a molecular analysis of 28 high- and low-risk HPV genotypes was performed in OOC samples of patients seen during the last 15-years in a Spanish tertiary care center. Results Of 115 odontogenic cysts with keratinization, 16 cases of OOCs were confirmed and evaluated. OOCs occurred predominantly in the mandible of males (mean age 36.06 ± 13.16 years). Swelling of the jaw followed by pain were the most common clinical symptoms, and 56.5% of the OOC cases were associated with an unerupted tooth. After a mean post-cystectomy follow-up of 3.8 years, only one recurrent case was observed, resulting in a verrucous cystic lesion that was considered premalignant after immunohistological examination. DNA extraction was successful from 14 of the 16 OOC cases. None of the primary OCCs or the single recurrent OOC were positive for HPV in the molecular analysis. Conclusions OOCs show a very limited potential for recurrence. Our results suggest that neither high- or low-risk HPV subtypes are likely to play a role in the etiology or neoplastic transformation of OOC, at least in the Spanish population.