Oral squamous cell carcinoma (OSCC) makes 85-95% of all malignances in the oral cavity. Increasing evidence shows that the Human Papillomaviruses (HPVs) are preferentially associated with some oropharyngeal and OSCCs, namely the genotype 16. The aim of the present study was to determine the prevalence and clinical implications of HPV16 infection in oral squamous cell carcinoma in population of Montenegro. This study included 60 patients with OSCC (localized on the lower lip, tongue or/and floor of the mouth), surgically treated at the Clinical Centre of Montenegro from 2012 to 2018. Surgically obtained formalin-fixed and paraffin-embedded specimens were used for histopathological analysis and HPV16 genome detection using standard Polymerase Chain Reaction (primers for detection of E6 gene). Each individual was further followed up for the period of three years and for different clinico-pathological characteristics, including disease free interval (DFI). The prevalence of HPV16 infection in OSCCs was 23.3% and the infection was significantly more common in female patients (P50.038). No significant correlation was detectable between HPV16 infection and the patients? age (P50.302), tumor site (P50.125), tumor grade (P50.363) and disease stage (P50.995). Observing the total sample the DFI was not significantly different for HPV16-positive versus HPV16-negative patients (P 5 0.427), but a gender-based difference in DFI was observed, with the significantly shorter DFI (Log Rank test, P 5 0.003) in HPV16 positive female patients compared to male patients (P 5 0.003). The results obtained in this study provide scientific evidence for the development of national HPV vaccination program in Montenegro.  Kulcsszavak: Human Papilloma Virus, HPV16 infection, oral cancer, HPV vaccine