Background: Agent Orange has been posited as an environmental risk factor for prostate cancer among United States Veterans. Prior studies have shown that Veterans with Agent Orange exposure are diagnosed at a younger age and at more advanced clinical stages. It is unknown if there are differences in somatic alterations among Veterans exposed to Agent Orange. Methods: Genomic alterations were identified from clinical tumor testing conducted from 2019 – 2022 in a large cohort of Veterans with metastatic prostate cancer diagnosed from 2001 – 2022. Primary prostate and metastatic carcinoma tissue specimens were submitted for Foundation Medicine tumor-only sequencing. Baseline demographics, clinical, and genomic alterations data were stratified by Veteran self-reported exposure to Agent Orange in accordance with an institutional review board approved protocol. Results: Of the 2673 Veterans with metastatic prostate cancer who underwent tumor-only genomic testing, 629 reported exposure to Agent Orange and 2044 were not exposed. After verification of military service records of Veterans with self-reported Agent Orange exposure to include only Veterans who served in the Vietnam War between 1962 – 1975 and Korean War between 1967 – 1971, 603 patients with self-reported Agent Orange exposure (22.8%) and 2044 without exposure (77.2%) were included in the analysis. On univariate analysis, TMPRSS2-ERG fusions were significantly more frequent in men who reported exposure to Agent Orange (35.3% vs 28.8%, p<0.01) after multiple hypothesis testing with Benjamini-Hochberg. Agent Orange exposure also correlated to higher rates of androgen receptor (AR) alterations (12.4% vs 9.5%, p=0.04) and FGFR1/2/3/4 alterations (3.2% vs 1.7%, p=0.02). There were no significant differences in alterations by Agent Orange exposure in TP53, CDK12, ERBB2, EGFR, BRCA, and genes implicated in the DNA damage response and repair (DDR), mismatch repair (MMR), and PTEN/PI3K/AKT pathways. On multivariable analysis controlling for race, age at diagnosis, smoking, secondary malignancies, and environment, only alterations in AR (OR 1.43, p=0.02) remained more frequent in Veterans exposed to Agent Orange. As expected, age at diagnosis (OR 0.98, p<0.001) and Black/African-American race (OR 0.33, p<0.001) were associated with decreased odds of TMPRSS2-ERG alterations. Conclusions: Agent Orange exposure may contribute to tumor somatic alterations in Veterans with prostate cancer. These findings hold potential prognostic and therapeutic implications for U.S. Veterans with metastatic prostate cancer.