Background: Spinal cord compression (SCC) from prostatic cancer is an oncologic emergency with significant negative impact on morbidity and survival. However, the molecular mechanisms involved in spinal metastases remains largely unclear. The aim of this study was to evaluate the histopathology, molecular profiles, and outcome in these patients. Methods: Twenty patients with magnetic resonance imaging-confirmed metastatic SCC from prostate cancer were identified at Dignity health Cancer Institute. Pathology slides were reviewed and the molecular analysis of 324 cancer-related genes was performed on tumor specimens using targeted next-generation sequencing. Characteristics including age, Gleason score, SCC anatomical site, time to diagnosis of SCC, gene alterations, number of lines of treatment and clinical outcome were analyzed. Results: At the time of diagnosis of SCC, the median age at diagnosis of SCC was 60.5 years old (range=50-76). The median PSA value was 626 ng/ml, 100% of patients have a Gleason score above 7, 30% of patients had visceral metastases. The thoracic spine affecting (15/20) patients is the most common site of SCC. Seventeen patients (75%) were initially treated with surgery combined with radiation therapy (RT), whereas 3 (15%) were managed with RT alone. At the time of this study, 11 patients remain alive (55%), median overall survival (OS) is 20 months, 18 months in treatment naive and 22 months in hormone refractory patients. Molecular analysis revealed gene mutations in all (100%) tumors, The most common gene alterations were PTEN (16%), followed by AR alterations AR (13%), TP53 (11%), TMPRSS2-ERG (8 %), BRCA1/2(4%), RB1(1%) and ATM (1%). Conclusions: Comprehensive genomic profiling revealed several molecular targets in patients with metastatic spinal cord compression from prostate cancer.