OBJECTIVES: This study aims to quantify the impact of (1) black box warning, (2) CMS National Coverage Determination (NCD), and (3) Risk Evaluation and Mitigation Strategies (REMS) on erythropoiesis-stimulating agents (ESAs) on-label and off-label utilization patterns among adult inpatients.  METHODS: Electronic health records in Cerner HealthFact database from January 2005 to June 2011 were used.  Eligible patients for ESA prescribing were categorized using ICD-9-CM codes and medication information.  The three patient categories were (1) on-label (ONS, conditions approved by the FDA); (2) off-label supported (OFS, strong clinical evidence for use in unapproved indications); and (3) off-label unsupported (OFU, low/no evidence supporting use in unapproved indications).  The likelihood of receiving ESAs was assessed using a generalized estimating equation approach with binary logistic regression technique, clustering for hospitals, and controlling for potential confounders. RESULTS: We identified 730,421 patients with ONS conditions (33,004 users, 4.5%), 505, 658 with OFS conditions (5,140 users, 1.0%), and 558,917 patients with OFU conditions (4,491 users, 0.8%).  Black box warning and REMS had no impact on the odds of receiving ESAs.  There was a significant decline in all three use categories the month following NCD.  ONS patients were 13% less likely to receive ESAs (OR 0.867, 95% CI 0.762, 0.986, p = 0.0299).  OFS patients were 20% less likely (OR 0.799, 95% CI 0.716, 0.891, p <0.0001) and OFU patients were 38% less likely to receive ESAs (OR 0.622, 95% CI 0.474, 0.817, p = 0.0006).  Age, gender, race, source of payment, admission type, clinical complexity, discharge disposition, and hospital size were significantly associated with on-label and off-label use. CONCLUSIONS: We demonstrated the relative impact of three safety interventions on on-label and off-label ESA use in the hospital settings.  Reimbursement change may have unintentionally reduced the likelihood of receiving ESAs in patients who could have otherwise benefited.