Therapy-related myelodysplastic syndromes and acute myelogenous leukemia (t-MDS/AML) comprise a poor-risk subset of MDS/AML. Large scale mutation profiling efforts in de novo MDS have identified mutations that correlate with clinical features but such mutations have not been investigated in tMDS/AML. Genomic DNA from 38 patient samples was subjected to high throughput PCR and sequenced for TP53, TET2, DNMT3A, ASXL1, IDH1, IDH2, EZH2, EED, SUZ12, RBBP4, and splicing factors SRF2, U2AF35, and SF3B1. We identified somatic mutations in 16/38 (42%) patients. TP53 mutations were the most common lesion, detected in 8/38 (21%) patients, followed by TET2 in 4/38 (10.5%). Cases with a TP53 mutation or loss of the TP53 locus had a worse overall survival compared to those with wild type and intact TP53 (8.8 months vs 37.4 months p=.0035).