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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.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.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.