Abstract Purpose: The purpose of this study is to investigate whether individuals with Ewing's sarcoma are at increased risk of developing other cancers. The presence of excess cancers in first-, second-, and third-degree relatives of ES cases is also investigated. Background: Ewing's sarcoma (ES) is a rare, aggressive bone cancer that affects children and young adults. In 85% of ES cases, a chromosomal translocation between the EWSR1 gene on chromosome 22 and the FLI1 gene on chromosome 7 is observed in somatic cells. In the remainder of cases, the EWSR1 gene fuses to other ETS family gene members. The resulting EWS/ETS fusion protein formed in ES cases dysregulates target genes–thereby promoting oncogenesis. Methods: The Utah Population Database (UPDB) is a population-based genealogy linked to both the Utah Cancer Registry and to hospital data from the University of Utah Health Sciences Center. We used the UPDB to calculate the relative risks (RR) of 35 cancer sites in ES cases and in their relatives. RR was calculated using age-, birth-state- (Utah vs. non-Utah), birth county- (urban vs. rural) and birth-year-specific cancer rates. Results: We identified 133 individuals with ES who had ancestors in the UPDB. Brain cancer and complex genotype/karyotype sarcomas were observed at significant excess in more than one ES case (RR = 10.26; 95% CI: 1.24, 37.05; RR = 28.33, 95%CI: 3.43, 102.33, respectively). Individuals with ES had 695 first-degree, 2129 second-degree, and 6285 third-degree relatives in the UPDB. RRs for four cancer sites were significantly elevated in first-degree relatives: prostate (1.75; 1.06, 2.94), female genital (6.38; 1.13, 23.06), brain (3.68; 1.26, 9.42), and lung (2.31; 1.01, 5.04). In second-degree relatives, there was a significantly increased risk of four cancers: Non-Hodgkins lymphoma (2.07; 1.16, 3.42), breast (1.47; 1.11, 2.01), malignant peripheral nerve sheath (15.63; 1.89, 56.45), and tongue (4.02; 1.10, 11.75). Lastly, third-degree relatives had a significantly increased risk for five cancer sites: acute lymphocytic leukemia (3.74; 1.75, 7.70), stomach (1.87; 1.17, 3.03), prostate (1.23; 1.04, 1.49), brain (1.86; 1.07, 3.24), and gallbladder (2.73; 1.08, 6.37). Conclusion: The increased risk of several cancers other than ES in ES cases and in their relatives suggests the possibility of an inherent genetic predisposition to mutagenesis that predisposes both to observed mutations and chromosomal rearrangements seen in ES cases and to additional cancers (primarily brain and prostate) in individuals who do not have ES. Citation Format: Diana Abbott, R. Lor Randall, Joshua Schiffman, Stephen Lessnick, Lisa A. Cannon-Albright. A population-based survey of excess cancers observed in Ewing's sarcoma and in their first-, second-, and third-degree relatives. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2748. doi:10.1158/1538-7445.AM2015-2748