<p>Women of transgender experience and transfeminine people (WTE/TFP) are disproportionately impacted by HIV, yet local data on syphilis seroprevalence and HIV-syphilis co-infection among Black and Latina WTE/TFP in Los Angeles County (LAC) remain limited. This study examined HIV and treponemal syphilis seroprevalence and identified correlates of HIV-syphilis co-infection among Black and Latina WTE/TFP in LAC. From August 2023 through June 2024, the National HIV Behavioral Surveillance (NHBS) in LAC recruited WTE/TFP using respondent-driven sampling. Among 352 non-Hispanic Black (<i>n</i> = 99) and Latina (<i>n</i> = 253) participants with valid HIV and treponemal syphilis test results, HIV seroprevalence was 42%, treponemal syphilis seroprevalence was 56%, and HIV-syphilis co-infection was 33%, indicating substantial overlap of the two epidemics. Structural vulnerability was widespread, including food insecurity (70%), incarceration history (46%), homelessness (39%), and unemployment (39%). Co-infection was unevenly distributed. In adjusted analysis, Black participants had a 70% higher prevalence of co-infection than Latina participants (aPR = 1.70, 95% CI 1.14–2.52), and methamphetamine use was associated with nearly twice the prevalence of co-infection (aPR = 1.89, 95% CI 1.22–2.94). Continued efforts to expand routine syphilis screening, timely staging and treatment, doxycycline post-exposure prophylaxis education and counseling, and integrated harm reduction services are vital to addressing this overlapping epidemic. These findings also support sustained investment in Black-centered, peer-led trans community organizations and trans-competent clinical care to better address the co-occurring HIV and syphilis burden among Black and Latina WTE/TFP in LAC.</p>