Background: Studies have suggested that statin use is associated with prostate cancer mortality. However, uncertainties exist in how the solubility profile of statins impact cancer outcomes. Lipophilic statins have greater accessibility in extrahepatic tissues, which may lead to stronger inhibitory effects on cancer cells, whereas hydrophilic statins exhibit greater hepato-selectivity and therefore less likely to cause drug interactions and adverse events. Abiraterone (ABI) and enzalutamide (ENZ) are antiandrogen agents used in metastatic castrate-resistant prostate cancer (mCRPC). In this study, we sought to examine whether statin usage and lipophilicity of statins is associated with survival benefits in mCRPC patients receiving ABI or ENZ. Methods: We conducted a nationwide retrospective cohort study of the Veteran Affairs population. Patients with mCRPC who received statin therapy one year prior to initiation of either ABI or ENZ between 9/10/2014 and 6/3/2017 were included and followed until April 2020. Statins were categorized as lipophilic (atorvastatin, simvastatin, lovastatin, fluvastatin, cerivastatin, pitavastatin) and hydrophilic (rosuvastatin and pravastatin). A cox proportional hazards model was used to estimate adjusted hazards ratio (aHR) with 95% confidence interval (CI) of overall survival after controlling for known prognostic factors including age, Charlson-Romano Comorbidity Index, use of bone-modifying agents, Body-Mass Index, and prostate specific antigen levels. Results: A total of 4919 patients (mean age 75.0 years) were included in our cohort. Of those, 969 patients (19.7%) received lipophilic statins and 452 patients (9.2%) received hydrophilic statins. After adjusting for known factors, statin use was not associated with improved overall survival (aHR 0.93; 95% CI 0.87 – 1.00). Similarly, the use of lipophilic statins (aHR 0.98; 95% CI 0.90 – 1.06) or hydrophilic statins (aHR 0.90; 95% CI 0.80 – 1.01) were not associated with improved overall survival in mCRPC. Conclusions: Our study found no differences in overall survival between mCRPC patients with statin use compared to those without statins. When analyzing statin lipophilicity, we saw a higher trend towards survival in the hydrophilic statin group compared to the lipophilic statin group, which contradicts the direct anticancer benefits of lipophilic statins, but neither group reached statistical significance. Further studies analyzing statin usage and types with specific outcome measures such as cardiovascular events, duration of antiandrogen therapy, and adverse events related to ABI or ENZ will support in optimal therapy choices for mCRPC.