Proliferative verrucous leukoplakia (PVL) is a very aggressive form of oral leukoplakia (OL) with high morbidity and mortality rates, hypothesised to be linked to HPV infection. This study aimed to determine the presence of HPV DNA in PVL in comparison with OL, and in relation to social-demographical variables (age, gender, smoking and drinking habits) in an Italian multi-centric hospital-based study. The study group consisted of 58 cases of PVL and 90 cases of OL as controls (47 homogeneous (H) and 43 non-homogeneous (non-H) form), both recruited from four Italian cohorts. HPV DNA was identified in exfoliated mucosal cells by nested PCR (nPCR) with MY09/MY11 and GP5+/GP6+ primer pairs and the HPV genotype determined by direct DNA sequencing. HPV DNA was found in 24.1% (14/58)of PVL and in 25.5% (23/90) of OL; there was thus no significant difference found between PVL and OL (both forms) for risk of HPV infection (OR=0.93; 95% IC:0.432-1.985). Similarly, in both groups of PVL and OL lesions, no statistic association was found between any demographical variable considered and HPV infection. HPV-18 was the most frequently detected genotype in all tissues, being found in 78.5% and 60.8% of HPV+ve PVL and OL, respectively. Other more rarely detected genotypes were HPV-16 (28.6% in PVL and 13% in OL), HPV-6 (17.4% in OL) and HPV-53 (8.8% in OL). PVL does not appear more likely to be associated to HPV infection than conventional OL lesions.