Background: AA are extremely rare tumors, with potentially aggressive clinical behavior. The characterization of the molecular alterations of the disease is poorly described, as well as its association with clinical outcomes. The present study aims to evaluate the prognostic influence of GA on overall survival (OS) of AA patients (pts). Methods: We performed a retrospective study involving AA pts at MD Anderson Cancer Center between October 2012 and April 2017 who underwent next-generation sequencing (NGS) (at least 45 genes), using either tumor tissue specimens or peripheral blood for cell-free DNA (cfDNA). GA identified by NGS and clinicopathological variables were correlated with OS. Survival curves were performed by the Kaplan-Meier method and compared with log-rank test. Multivariate analysis of prognostic factors was performed by the Cox model. Results: A total of 78 pts were identified, of which 35 had died (45%) in a median follow-up time of 4.8 y. The majority of pts presented with stage IV disease (72%); 46% underwent cytoreductive surgery (CRS) + HIPEC. Tissue-based and cfDNA-based sequencing were performed on 73% and 23% of the pts, respectively, and 4% had both. The most frequent GA were KRAS (62%), TP53 (36%), GNAS (28%), SMAD4 (18%), PIK3CA (16%), and APC (15%). By univariate analysis, stage, tumor grade, and CRS + HIPEC demonstrated prognostic value (p < 0.05). Multivariate subset analysis of stage IV pts adjusting for age, tumor grade (TG), CRS + HIPEC, KRAS, GNAS, and p53, demonstrated that poorly differentiated tumors and a KRAS mutated tumor resulted in worse OS (HR: 12.1 and HR: 3.9, respectively, both with p < 0.05) and CRS + HIPEC resulted in an improved OS (HR: 0.32, p < 0.05). Conclusions: Our analysis indicates that TG and the presence of the KRAS mutation are poor prognostic factors in the OS of pts with AA. CRS + HIPEC offers survival advantage. Molecular characterization and prognostication of these rare tumors may help guide therapy. These findings need validation, thereby continued evaluation in a larger population and utilizing a wider molecular platform is ongoing.