Background: Data regarding predictive biomarkers in Appendiceal Adenocarcinoma (AA) is scarce. GNAS mutations, frequent in mucinous AA, have been linked with poor objective response (OR) to chemotherapy. We hypothesize that activating GNAS mutations are associated with differential outcomes for metastatic AA treated with chemotherapy. Methods: We reviewed the records of AA patients (pts) seen between 2013 and 2023. Pts who received 5-Flurouracil/Capecitabine (5-FU/Cape) based chemotherapy for at least 3 months (m) in the metastatic/recurrent setting (no chemotherapy for localized AA in prior 12 m) and had data available for GNAS mutations were included. The primary outcome was disease event-free survival (dEFS): the time from first dose of 5-FU/Cape given for metastatic/recurrent AA to the earliest disease event: death, radiographic recurrence in pts with complete cytoreduction (CC0), or clinical/radiographic progression. The secondary outcome was overall survival (OS). Associations between GNAS status, clinicopathologic features, and study outcomes were assessed using univariable and multivariable (for variables with p values < 0.2) Cox proportional hazards regression analysis. Results: 48 pts were eligible. GNAS activating mutations (excluding variants of uncertain significance) were seen in 18/48 (37.5%), all at the R201 hotspot (R201H = 15, R201C= 3). Clinicopathologic characteristics between activating GNAS mutated (GNAS^mt) and GNAS wild-type (GNAS^wt) groups are compared in Table 1. Over a median follow-up of 29.83 m, GNAS^mt pts had worse dEFS (adjusted HR [aHR], 5.62; 95% CI, 1.65 – 19.12; p = 0.006), after adjusting for CC0 reduction, histology (mucinous vs. non-mucinous), and synchronous metastases (vs. metachronous). CC0 reduction (aHR, 0.43; 95% CI, 0.21 – 0.88; p = 0.02) and synchronous metastases (aHR, 0.30; 95% CI, 0.12 – 0.74; p = 0.009) were also associated with improved dEFS. There was no significant difference in OS between GNAS^mt vs. GNAS^wt pts (HR, 0.82; 95% CI, 0.39 – 1.73; p = 0.61). Conclusions:GNAS mutated metastatic AAs show worse disease event free survival with chemotherapy which aligns with historic OR data. A previously reported survival benefit of GNAS mutations in AA, likely due to favorable disease at baseline (see table), is negated in the setting of metastatic disease treated with chemotherapy. Evaluating GNAS status as a predictive biomarker for AA is warranted.