Background: Appendiceal adenocarcinoma (AA) encompasses a heterogenous mix of histologic subtypes and frequently presents with peritoneal metastases. Data regarding the risk of relapse after surgical resection in patients with localized AA (stages I–III) is limited. More accurate evaluation of features predictive of relapse is critical to counsel patients, determine follow-up, and guide decisions regarding adjuvant therapy. Methods: The Foundry software platform was used to query the MD Anderson Cancer Center (MDA) Electronic Health Record database to identify and extract clinical information from AA patients presented to MDA from 2004 to 2023. Results: We identified 296 patients with localized AA, split into two cohorts: patients who underwent surgery at MDA (n=133) and patients with surgery at an outside institution later referred to MDA (n=163). The most common histologic subtypes were mucinous (n=124, 41.9%) and goblet (n=121, 40.9%) with less frequent colonic-type (n=42, 14.2%) and signet ring cell (SRC, n=9, 3%). With a median follow-up of 47 months, the relapse rate (RR) for the MDA surgical cohort was only 6% (n=8), with a median time to relapse of 24 months (range=8-74). Evaluating all 296 localized AA patients, histologic subtype was significantly associated with risk of relapse, with goblet AAs having lowest risk (6%, n=7), followed by colonic-type (12%, n=5), mucinous (27%, n=33), and SRC (44%, n=4; overall P< 0.001), with a median time of relapse of 26 months (range=3-96). Patients with a positive LN, higher grade, and/or higher T stage showed a higher RR (Table). Use of adjuvant chemotherapy (AC) was not associated with RR in our cohort, with odds ratio trending towards increased risk of relapse (14.4% vs 19.2%, OR=1.4, 95% CI=0.76-2.6; P=0.27). Restricting to only high-risk patients (poorly differentiated, LN-positive, and/or T4, n=205), similar results were observed with 18.4% (n=17) relapsed without AC vs 19.4% (n=22) relapsed with AC (OR=1.06, 95%CI=0.52-2.15; P=0.85). AC was also not associated with improved RFS (HR=1.2, 95%CI=0.63-2.2, P=0.59). Conclusions: Patients with localized AA who undergo surgical resection have a low risk of relapse, especially those with goblet AA. This retrospective analysis did not identify a benefit from adjuvant chemotherapy. Considering the clear histologic and molecular differences between AA and CRC, these data call into question the current practice of applying CRC data to guide AC decisions in AA. Prospective clinical trials of AC in AA, stratified by histologic subtype, are urgently needed.