Background The Accreditation Council for Graduate Medical Education (ACGME) implemented duty hour regulations for residents in 2003 and again in 2011. While previous studies showed no systematic impacts in the first 2 years post-reform, the impact on mortality in subsequent years has not been examined. OBJECTIVE To determine whether duty hour regulations were associated with changes in mortality among Medicare patients in hospitals of different teaching intensity after the first 2 years post-reform. DESIGN Observational study using interrupted time series analysis with data from July 1, 2000 to June 30, 2008. Logistic regression was used to examine the change in mortality for patients in more versus less teaching-intensive hospitals before (2000–2003) and after (2003–2008) duty hour reform, adjusting for patient comorbidities, time trends, and hospital site. PATIENTS Medicare patients (n  = 13,678,956) admitted to short-term acute care non-federal hospitals with principal diagnoses of acute myocardial infarction (AMI), gastrointestinal bleeding, or congestive heart failure (CHF); or a diagnosis-related group (DRG) classification of general, orthopedic, or vascular surgery. MAIN MEASURE All-location mortality within 30 days of hospital admission. KEY RESULTS In medical and surgical patients, there were no consistent changes in the odds of mortality at more vs. less teaching intensive hospitals in post-reform years 1–3. However, there were significant relative improvements in mortality for medical patients in the fourth and fifth years post-reform: Post4 (OR 0.88, 95 % CI [0.93–0.94]); Post5 (OR 0.87, [0.82–0.92]) and for surgical patients in the fifth year post-reform: Post5 (OR 0.91, [0.85–0.96]). CONCLUSIONS Duty hour reform was associated with no significant change in mortality in the early years after implementation, and with a trend toward improved mortality among medical patients in the fourth and fifth years. It is unclear whether improvements in outcomes long after implementation can be attributed to the reform, but concerns about worsening outcomes seem unfounded.