Background People living with HIV (PLWH) are more susceptible to persistent human papilloma virus (HPV) infection; however, data regarding oral HPV burden among youth with or without perinatal HIV exposure or infection in sub-Saharan Africa remain scarce. This study characterized how dental, immune and behavioral factors contribute to oral HPV susceptibility among youth and mothers across varying HIV exposure groups. Methods This baseline analysis leveraged data from a prospective cohort in Nigeria. Participants were categorized at recruitment as HIV-infected (HI), HIV-uninfected (HU), HIV-exposed uninfected (HEU), or HIV-unexposed uninfected (HUU). Standardized questionnaires captured behavioral data, and comprehensive dental examinations assessed DMFT (Decayed, Missing, Filled Teeth), OHIS (Oral Hygiene Index Simplified), and GIS (Gingival Inflammation Score). Oral rinse specimens were tested for oral HPV DNA (Seegene assay). Blood samples were collected from all participants for immune parameters (CD4/CD8). Multivariable regression and machine-learning approaches were used to identify key predictors across immunologic, behavioral, and oral-health domains. Results Although overall oral HPV prevalence was low, detection significantly differed across study groups. Oral HPV DNA was exclusively detected in mothers living with HIV (N=8/404) and 7 youth (N=7/671; HI = 4, HEU = 2, HUU = 1). Among youth, HPV correlated with lower CD4/CD8 ratios and poorer oral health In mothers, HPV positivity was linked to earlier sexual debut and lower CD4 counts. Machine learning models revealed distinct age-specific patterns; dental metrics and immune measures were the primary predictors in youth, outranking traditional behavioral factors whereas immune features and dental indices dominated in mothers. Conclusions Despite low prevalence, oral HPV clustered among PLWH and was strongly associated with modifiable dental indices. These findings identify oral health as a potential determinant of HPV susceptibility and underscore the importance of integrating oral health promotion within HIV care to elucidate and mitigate pathways linking oral health, immunity, and viral persistence.