Abstract Background: According to cancer registry data, nearly 20% of Endometrial Cancer (EC) cases in the US are second or higher-order primary cancers. Little is known in regard to the epidemiology of EC as a Second Primary (ECSP) cancer. Purpose: To compare ECSPs and EC as a first primary in relation to histological types and cause- specific survival; examine survival of ECSP according to original primary site, and treatment received for the first primary. Methods: All cases of EC diagnosed from 2005-2016 were obtained from the Florida Cancer Data System. Chi-square tests, Kaplan-Meier methods and Cox Regression were used in the analysis. Results: Of 9,002 initial ECSPs, 73% were not “clinically independent”, i.e. without treatment distinctions between first and second cancers. These included ECSPs of different histologies from a first EC, and ECSPs following ovarian and cervical cancers (<1 year). After excluding these, there were 2,401 ECSPs and 37,128 ECs as a first primary; 1,260 ECSPs followed breast cancer (BC), 299 followed colorectal cancer (CRC), and other sites(n=842). The 5-year, age-standardized cause-specific survival was 72.2% (95%CI: 71.8-72.7) for first ECs and 60.7% for ECSPs (95%CI: 58.5-63.0). However, after adjusting for age, race/ethnicity, histology, and stage there was no significant difference between ECSP and first EC (HR 0.92, 95%CI: 0.83-1.03). Post- colorectal ECSPs had lower 5-year survival (55.3%, 95%CI: 48.9-61.7) than post- breast cancer ECSPs (64.8%, 95%CI: 61.8-67.9), and significantly higher risk of EC- specific death (HR 1.78, 95%CI:1.23-2.58) in multivariable analysis. Lastly, women who had chemotherapy for both ECSP and a preceding BC did not have a higher EC- specific risk of death (HR 0.79, 95% CI: 0.46-1.36) compared to those who only received chemotherapy for EC as a first primary. Conclusions: ECSP survival is similar to that of EC as a first primary. However, ECs post-CRC may constitute a population of interest with much worse survival than those post-BC. There was no information to separately assess Lynch syndrome cases or those receiving tamoxifen as part of BC treatment. Lastly, chemotherapy for a previous BC does not seem to affect the effectiveness of chemotherapy for ECSPs. Further research is needed in the epidemiology of second cancers. Citation Format: Heidy N. Medina, Matthew P. Schlumbrecht, Paulo S. Pinheiro. Epidemiology of endometrial cancer as a second primary malignancy in Florida [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-150.