Background: FBXW7 functions as a ubiquitin ligase tagging dominant oncogenic proteins such as cyclin E, MYC, Jun and Notch for degradation by the proteasome system. FBXW7mt are noted throughout the gene and have been shown to have differential effects depending on location and type. Recent data suggests that missense mt lead to greater loss of FBXW7 function than nonsense or truncation mt but the clinicopathological factors associated with FBXW7 missense mt and clinical outcomes in mCRC have not been described. Methods: Data from pts with mCRC whose tumors were evaluated by next generation sequencing for hotspot mt through the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) program at MD Anderson Cancer Center were obtained. Alterations in FBXW7 were identified and their implications on clinical, pathological features and overall survival (OS) were evaluated. Results: Of 854 mCRC pts in the ATTACC dataset, 574 had data on FBXW7 of which 45 pts (7.8%) had mt. Of these, 38 were missense mt while others were nonsense (5), insertions or deletions (1 each). R465H mt in exon9 and R497Q mt in exon10 were the most common missense mt (15.8% each). None of the clinicopathological features including age, gender, tumor site & grade, KRAS, BRAF, PIK3CA mt or microsatellite status were associated with FBXW7 missense mt. Pts with FBXW7 missense mt tumors had significantly inferior OS compared with pts with FBXW7 wild type tumors in both univariate (median OS 36.2 months, mos 95% confidence interval, CI 18.7-38.5 in mt vs median OS 47.5 mos 95% CI 44.2-50.9 mos; p = 0.003) and multivariate analyses after correcting for other known prognostic factors including KRAS, BRAF status and tumor grade (HR = 1.8, 95%CI: 1.14-2.86; p = 0.01). In contrast, other alterations in FBXW7 did not appear to impact prognosis (median OS 42.9 mos, 95% CI 21.1 – 64.8 mos). Conclusions: To date, this is the largest clinical dataset of FBXW7 missense mt which showed negative prognostic impact on survival in mCRC without any association with other known prognostic factors. Further studies on identification of downstream pathways underlying this worse prognosis and potential therapeutic targets are required.