BACKGROUND: We explored regional variation in 30-day ischemic stroke mortality and readmission rates and the extent to which regional differences in patients, hospitals, healthcare resources, and a quality of care composite care measure explain the observed variation. METHODS AND RESULTS: This ecological analysis aggregated patient and hospital characteristics from the Get With The Guidelines-Stroke registry (2007-2011), healthcare resource data from the Dartmouth Atlas of Health Care (2006), and Medicare fee-for-service data on 30-day mortality and readmissions (2007-2011) to the hospital referral region (HRR) level. We used linear regression to estimate adjusted HRR-level 30-day outcomes, to identify HRR-level characteristics associated with 30-day outcomes, and to describe which characteristics explained variation in 30-day outcomes. The mean adjusted HRR-level 30-day mortality and readmission rates were 10.3% (SD=1.1%) and 13.1% (SD=1.1%), respectively; a modest, negative correlation (r=-0.17; P=0.003) was found between one another. Demographics explained more variation in readmissions than mortality (25% versus 6%), but after accounting for demographics, comorbidities accounted for more variation in mortality compared with readmission rates (17% versus 7%). The combination of hospital characteristics and healthcare resources explained 11% and 16% of the variance in mortality and readmission rates, beyond patient characteristics. Most of the regional variation in mortality (65%) and readmission (50%) rates remained unexplained. CONCLUSIONS: Thirty-day mortality and readmission rates vary substantially across HRRs and exhibit an inverse relationship. While regional variation in 30-day outcomes were explained by patient and hospital factors differently, much of the regional variation in both outcomes remains unexplained.