Abstract Human papillomavirus (HPV) is the most common malignancy worldwide, accounting for more than 70% of oropharyngeal cancers. People living with HIV (PWH) are disproportionately affected by HPV infection and are at higher risk of HPV-associated oral complications, dysplasia, and cancer, even with suppressive antiretroviral therapy (ART), suggesting that ART may not fully recover oral HPV-specific immunity. Particularly, Puerto Rico (PR) has a significant burden and disparity for both HIV and HPV infections and related cancers. Dysbiosis of the oral microbiome occurs in PWH, characterized by a decrease in diversity, and a change in the abundance of microbial products important for human health and disease. The relationship of the oral microbiome with HPV infection is poorly understood, particularly in PWH. In this study, we measured oral microbial diversity and products, such as short chain fatty acids (SCFA), in saliva and evaluated them in the context of HPV infection in PWH. We evaluated 48 sexually active PWH (17 HPV+ and 31 HPV-) from a community clinic in San Juan, Puerto Rico. Oral rinse samples were collected and analyzed for HPV infection and genotyped using the DNA ELISA kit HPV SPF10 and RHA kit HPV SPF10-LiPA25 which detects 40 HPV subtypes. We characterized oral prokaryotic communities by sequencing 16S rDNA and quantified the levels of SCFAs (acetate, propionate, iso-butyrate, butyrate, iso-valerate, valerate, and hexanoate) in saliva using GC-MS. Statistical analyses of bacterial diversity and levels of SCFA were assessed in relation to HPV status using R-statistical software. PWH had a median CD4 count of 738 cells/µL [IQR: 649-887]. PWH with HPV had a 73% (11/15) of high-risk HPV genotypes, with HPV-18 being the most prevalent subtype (6/17). While there was no significant difference in alpha diversity (Shannon: p=0.23 and Observed features: p=0.28), bacterial communities were clustered according to HPV status using a Bray-Curtis dissimilarity index. Furthermore, PWH with HPV showed higher levels of butyrate (p=0.07) and significantly lower levels of hexanoate (p=0.05) in saliva. Particularly, PWH with the HPV-18 subtype had lower levels of hexanoate than other HPV subtypes and HPV- PWH (p=0.03). Overall, these findings suggest that the oral microbiome and SCFA are associated with HPV infection and the presence of specific HPV subtypes. While a difference in bacterial diversity might not be driving HPV infection, different bacterial groupings might affect the abundance of specific SCFA, such as butyrate, which can contribute to local inflammation and periodontal tissue damage, providing an ideal environment for HPV infection and persistence. Understanding how the oral microbiota could facilitate HPV infection and other comorbidities in PWH is crucial for the development of cancer prevention and reduce the burden of HPV-associated malignancies in PWH. Furthermore, HPV vaccine-oriented and oral health educational interventions should target this high-risk group. Citation Format: Yabdiel A. Ramos Valerio, Eduardo S. Perez Delgado, Maria M. Sanchez, Ramon F. Gonzalez Garcia, Ana P. Ortiz Martinez, Magaly Martinez Ferrer, Josue Perez Santiago. The oral microbiome and short chain fatty acids as contributors to oral HPV disparities in Puerto Rican people with HIV [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C135.