Background: Recent work has shown an association between longer survival and aspirin use in colorectal cancer (CRC) patients with mutated PIK3CA. It has been hypothesized that this survival advantage could occur via blocking the PI3K pathway and allowing apoptosis of mutated cancer cells. The goal of this work is examine the use of aspirin and outcome in CRC patients with PI3KCA mutation. Methods: PIK3CA mutation status was assessed in paraffin-embedded tumor samples from 471 CRC patients between 1998-2010. PIK3CA mutation was assessed by exome sequencing using an Illumina Next Generation (NGS) platform with 50-100X coverage on all patients. The BWA/GATK pipeline was used to identify variants and indels. Because matched normal samples were not available for comparison to identify somatic mutations, filtering of normal variants was performed using 1000 Genomes. The usage of aspirin was collected retrospectively with electronic chart review. Results: Out of 471 patients, 73 were found to have unique PIK3CA mutations by NGS (15.4%). The most common mutations were found at codon 9 (38%) and codon 20 (21%). Patients had a median follow up of 47 months. Initial stage at diagnosis for PIK3CA mutants were as follows: 11 pts were stage I, 31 pts were stage II, 24 pts were stage III and 16 patients were stage IV. Of patients who died, those taking ASA had a 5% cancer related mortality compared to 23% cancer related mortality in non-ASA users. In contrast, the non-cancer related mortality was 25% in ASA users and only 8% in non-ASA users. Cancer specific rates for five year survival were 90% in the ASA group and 57% in the non-ASA group for all stages. In stage IV patients, there was 80% five year survival in the ASA users and 32% in the non-ASA group. Conclusions: There was a trend toward improvement in five year survival for colorectal cancer patients with PIK3CA mutations who used ASA. This trend persisted even in stage IV patients. Notably, non-cancer related deaths were higher in the ASA users, most likely secondary to medical comorbidities that necessitated ASA use. As follow up continues and this data set matures, future work will focus on validating these preliminary results and relating specific PIK3CA mutations to ASA response.