Background: Metastatic appendiceal adenocarcinoma (AAC) is a heterogenous disease and a large proportion of patients present with diffuse metastases in the peritoneal cavity. Cytotoxic and targeted therapies are typically extrapolated from colorectal adenocarcinoma (CRC), however, the efficacy is not well studied. Herein we investigated the genetic profiles of these tumors in an effort to identify molecular characteristics and potentially actionable mutations, as well as the response to anti-EGFR therapy in RAS/BRAF wild type (wt) AAC. Methods: We identified patients (pts) with ACC treated at MSKCC from 2002 to 2016 who had undergone molecular profiling, either by next generation sequencing using our MSK-IMPACT platform, or by MALDI-TOF mass spectroscopy genotyping (Sequenom). MSK-IMPACT tumors and matched normal samples were analyzed on a 410 gene panel. Sequenom provided an 8 gene panel including KRAS, NRAS, BRAF, and PIK3CA. Via an IRB approved waiver, we collected tumor histology and evaluated those who were RAS/RAF wt and were treated with anti-EGFR therapy. Results: To date, we identified a total 109 AAC patients, of whom 60 had Sequenom testing and 49 had MSK-IMPACT. Among pts analyzed with MSK-IMPACT, 34 had mucinous adenocarcinoma, 6 adenocarcinoma, 9 adenocarcinoma ex goblet cell carcinoid. In total 194 alterations were identified with a median 3.9 alterations/patient (range 0-10). Alterations were seen most commonly in KRAS (57%), GNAS (33%), TP53 (29%), and SMAD4 (6%). Potentially treatable alterations were present in 12% of patients and included BRAF V600E (1), MTOR (2), ERBB2 (1) and NTRK(2). Of the total 109 pts, 51 (47%) were RAS/BRAF wt. Of those, 12 evaluable patients received anti-EGFR therapy with either panitumumab or cetuximab. There were no responders. Conclusions: Mutational sequencing in AAC indicates that 12% have mutations in genes such as BRAF V600E, MTOR, ERBB2 and NTRK with the potential to expand investigational options. Additionally, in RAS/BRAF wt pts, panitumumab/cetuximab does not appear to have therapeutic efficacy comparable to historic controls in RAS/RAF wt CRC.