Background: WNT signaling is abnormal in many inherited and acquired colorectal cancers, through mutations in APC and other components of the pathway including beta catenins and AXINs. Aspirin and other COX-2 inhibitors have been hypothesized to decrease WNT pathway activity in preclinical models, potentially leading to improved survival. We evaluated APC and WNT pathway mutations as potential prognostic and predictive biomarkers for ASA use in a cohort of colorectal cancer patients. Methods: We analyzed tumor samples collected from 468 CRC patients diagnosed between 1998 and 2010 as part of a multi-institutional observational study. We performed targeted exome sequencing using the Illumina NGS platform with 50-100X coverage of mutations. The BWA/GATK pipeline was used to identify variants and indels. Matched normal samples were not available for comparison to identify somatic mutations, so filtering of normal variants was performed using 1000 Genomes. One or 2 mutations in the APC gene were counted as mutant. Additional WNT pathway mutations included AXIN1, AXIN2, CTNNB1, WNT1, and WNT2. Variants identified in 1000 Genomes with an MAF <0.01 were filtered. ASA use data was collected through retrospective chart review. Results: MSI-H tumors were excluded. 356 patients were eligible for analysis. 258 patients had APC mutations and 20 patients had other WNT pathway mutations including CTNNs, WNTs, AXINs, and TCF7L2. 140 patients had metastatic disease. Aspirin users had a median age of 70 compared to non-users at 63. Patients with APC mutations had improved overall survival compared to wild type patients for early stage disease (p = 0.03) with a trend towards improvement in survival for metastatic patients. Additional WNT pathway mutations did not strengthen this relationship. ASA use was not associated with improved OS in the APC or WNT pathway mutant patients. Conclusions: In this population, APC mutations had positive prognostic value, which was more pronounced in early stage disease. There was limited predictive value for ASA use in APC mutant patients. However, aspirin users tended to be older which might have confounded the association.