Examining the current incidence rates of HIV and STIs among racial and ethnic minority and rural residents is crucial to inform and expand initiatives and outreach efforts to address disparities and minimize the health impact of these diseases. A retrospective, cross-sectional study was conducted using Medicaid administrative claims data over a 2-year period (July 2019-June 2021) in South Carolina. Our main outcomes of interest were claims for chlamydia, gonorrhea, syphilis, and HIV. Any beneficiary with at least one claim for a relevant diagnosis throughout the study period was considered to have one of these diseases. Descriptive analyses and multivariable regression models were used to estimate the association between STIs, HIV, race and ethnicity, and rurality. Overall, 158,731 Medicaid beneficiaries had at least one medical claim during the study period. Most were female (86.6%), resided in urban areas (66.6%), and were of non-Hispanic Black race/ethnicity (42.6%). In total, 6.3% of beneficiaries had at least one encounter for chlamydia, 3.2% for gonorrhea, 0.5% for syphilis, and 0.8% for HIV. In multivariable models, chlamydia, gonorrhea, and HIV claims were significantly associated with non-Hispanic Black or other minority race/ethnicity compared to non-Hispanic white race/ethnicity. Rural residents were more likely to have a claim associated with chlamydia and gonorrhea compared to urban residents. The opposite was observed for syphilis and HIV. Providing updated evidence on disparities in STIs and HIV among racial/ethnic minority and rural populations in a southern state is essential for shaping state Medicaid policies to address health disparities.