The non-metastatic castration-resistant prostate cancer (nmCRPC) treatment landscape has evolved following the approval of second-generation androgen biosynthesis (abiraterone) and receptor (enzalutamide) inhibitors. Skin rash, fractures and central nervous system (CNS) adverse events (AEs) have been reported among patients treated with these drugs. This analysis was conducted to estimate the economic burden of AEs among nmPC patients treated with abiraterone, enzalutamide, or bicalutamide (“study drugs”). NmPC patients switching to/adding a “study drug” ≥1 year after medical/surgical castration were identified in the MarketScan database (2012-2017). Patients with a claim for a prostate-specific antigen test or an oncologist visit ≤6 months before “study-drug” initiation; no hormonal therapies (except castration) or metastasis claim prior to starting “study drug”; and ≥3-month metastasis-free follow-up on “study drug” were included. Patients were categorized by presence of any of 18 CNS AEs, skin rash, fractures or no AEs. Annual healthcare resource use and costs were compared across groups (CNS AEs vs. no CNS AEs; composite AEs [defined as CNS AE, skin rash, fracture] vs. no AEs) using propensity-score weighted generalized linear models. 532 patients (Medians: Age:74 years; Follow-up:9 months) were included (bicalutamide: 477 (89.7%), enzalutamide: 23 (4.3%), abiraterone: 32 (6.0%)). 38% and 46% of patients experienced CNS AEs or the composite AEs, respectively. Compared to patients without CNS AEs, patients with CNS AEs had significantly higher per-person annual inpatient (0.34 vs 0.09), emergency room (0.90 vs 0.24), and outpatient (26.2 vs 18.4) visits and higher inpatient ($7,537 vs $2,844) and total ($51,116 vs $32,594) costs. Comparable results were observed for patients with the composite AEs vs no AE. NmPC patients treated with bicalutamide/abiraterone/enzalutamide have a high prevalence of CNS AEs and significant economic burden (incremental annual cost of $18,000/patient). Novel agents with better risk-benefit profiles may lower this economic burden and improve quality of survival.