Background: Primary and secondary (P&S) syphilis lesions may double HIV transmission risk, highlighting the importance of expeditious diagnosis and treatment of syphilis, especially where HIV incidence is highest such as among jurisdictions prioritized by the Ending the HIV Epidemic (EHE) initiative. Data describing characteristics of reported P&S syphilis cases by EHE designation are limited. We evaluated P&S syphilis cases in EHE and non-EHE areas reported to CDC via the National Notifiable Diseases Surveillance System (NNDSS) to inform ongoing syphilis and HIV prevention and control activities. Methods: We reviewed 2020 P&S syphilis cases reported via NNDSS from 50 states; Washington, D.C.; and Puerto Rico to determine what proportion were reported from EHE areas (48 counties; San Juan, Puerto Rico; Washington, D.C.; and seven states) and non-EHE areas. We also ranked P&S syphilis case counts by county and compared EHEdesignated counties and non-EHE counties, and stratified these cases by sex and sex of sex partners category (gay, bisexual, and other men who reported sex with men [MSM]; men who reported sex with women only [MSW]; and women) to determine how proportions of cases varied. We excluded P&S syphilis cases with unknown sex and from men with unknown sex of sex partners. Results: There were 33,939 P&S syphilis cases reported with known sex and sex of sex partners in 2020. While EHE areas accounted for 37% of the overall U.S. population, these areas reported 57% of all P&S syphilis cases with known sex and sex of sex partners in 2020. When stratifying P&S syphilis case counts by sex of sex partners category, 61%, 53%, and 53% of cases reported among MSM, MSW, and women respectively were from EHE areas. The top 20 counties for total P&S syphilis case counts in 2020 were EHE areas, and all but one of the 48 EHE-designated counties were in the top 100 counties for P&S syphilis case counts. Conclusions: The disproportionate burden of P&S syphilis in EHE areas and the linkage between syphilis and HIV highlight the importance of early recognition and prompt treatment of syphilis and offer opportunities for engagement in HIV prevention and treatment services. [ABSTRACT FROM AUTHOR]