Background: Endometrial cancer is the most common gynecologic malignancy in developed countries with over 60,000 new cases diagnosed in the United States each year. Adjuvant therapy is often omitted for low-risk, early-stage disease (FIGO stage IA, grade 1) but 1 in 20 women suffer recurrence after surgery alone. Hence, there is an important need for biomarkers of recurrence in this population to guide therapeutic management. Methods: We retrospectively analyzed 74 patients with FIGO stage 1A, grade 1 endometrial endometrioid adenocarcinoma treated at our institution with hysterectomy alone between 2009-2016. All patients had targeted genomic assessment of their tumors (OncoPanel; somatic mutations, copy number variations and structural variants across 300 cancer genes). The primary outcome of interest was freedom from recurrence (FFR). Outcomes were compared by the logrank test and survival estimates calculated by Kaplan-Meier method. Results: We identified 14 patients who recurred at a median time of 23.6 months after surgery and 60 patients without recurrence at a median follow-up of 38.9 months. Age (median 57 years; log-rank p = 0.91) and BMI (median 31 kg/m2; log-rank p = 0.21) were not associated with risk of recurrence. The median somatic mutation count in the cohort was 8. Patients with more than 8 somatic mutations had a significantly higher risk of recurrence (3-year FFR: 74% vs 90%; log-rank p = 0.004). At the level of individual genes, there were four genes that were significantly associated with recurrence: CTNNB1 (p = 0.046), RHPN2 (p = 0.020), SF1 (p = 0.044), SQSTM1 (p = 0.034). Patients with a mutation in one or more of these four genes had a significantly higher risk of recurrence (3-year FFR: 62% vs 93%; log-rank p = 0.0004). Conclusions: We have identified overall somatic mutation burden and mutations in a subset of four genes (CTNNB1, RHPN2, SF1, SQSTM1) as determined by a validated 300-gene panel used in routine clinical practice as prognostic biomarkers for patients with low-risk, early-stage endometrial endometrioid adenocarcinoma. These patients may benefit from the addition of adjuvant therapy. Validation with larger cohorts and prospective studies is warranted.