Background: Scalable next generation sequencing (NGS) technologies have enabled incorporation of precision oncology into clinical practice, informing treatment decisions based on tumor genomics. The Veterans Health Administration (VHA) is the largest integrated healthcare system in the U.S., serving a higher percentage of rural patients (36%) than the national average (14%). To implement and standardize the practice of precision oncology across a diverse healthcare system, the VHA established the National Precision Oncology Program (NPOP). Methods: Tumor or peripheral blood specimens were collected from Veterans with advanced solid tumors who were eligible for treatment with targeted or immunotherapeutic drugs. Specimens were sequenced using cancer gene panels at two commercial laboratories. Annotated results were generated by the vendors and independently using IBM Watson for Genomics. Levels of evidence treatment recommendations were based upon OncoKB criteria. Results: Between July 2016 and June 2018, 3713 samples were collected from 72 facilities; the sequencing success rate was 86%. The majority of samples came from males with lung, prostate and colorectal cancers. Thirty-four percent of samples submitted were from rural patients. The most commonly mutated genes included TP53, ATM and KRAS. Over 70% of samples sequenced had at least one actionable mutation, and clinical trials were the recommended option in over 50%. The most frequent therapies prescribed in response to NGS testing were immune checkpoint inhibitors, EGFR kinase inhibitors and PARP inhibitors. Interestingly, prostate cancers among Veterans had a higher frequency of mutations in genes associated with a neuroendocrine phenotype compared with the general population. Conclusions: Implementation of precision oncology into clinical practice is feasible across the diverse VHA system, including rural community sites. Veterans have unique occupational exposures that might inform underlying causes of distinct mutational signatures identified here. Our results highlight the importance of increasing the availability of clinical trials for Veterans.