Background: Heart failure (HF) is the leading cause of hospitalization for Medicare beneficiaries. Nearly half of all HF patients have diastolic HF or HF with preserved ejection fraction (HF-PEF). Because these patients were excluded from major randomized clinical trials of neurohormonal blockade in HF there is little evidence about their role in HF-PEF. Methods: The aims of the American Recovery & Reinvestment Act-funded National Heart, Lung, and Blood Institute-sponsored "Neurohormonal Blockade and Outcomes in Diastolic Heart Failure" are to study the long-term effects of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists in four separate propensity-matched populations of HF-PEF patients in the OPTIMIZE-HF (Organized Program to Initiate Life-Saving Treatment in Hospitalized Patients with Heart Failure) registry. Of the 48,612 OPTIMIZE-HF hospitalizations occurring during 2003-2004 in 259 U.S. hospitals, 20,839 were due to HF-PEF (EF ≥ 40%). For mortality and hospitalization we used Medicare national claims data through December 31, 2008. Results: Using a two-step (hospital-level and hospitalization-level) probabilistic linking approach, we assembled a cohort of 11,997 HF-PEF patients from 238 OPTIMIZE-HF hospitals. These patients had a mean age of 75 years, mean EF of 55%, were 62% women, 15% African American, and were comparable with community-based HF-PEF cohorts in key baseline characteristics. Conclusions: The assembled Medicare-linked OPTIMIZE-HF cohort of Medicare beneficiaries with HF-PEF with long-term outcomes data will provide unique opportunities to study clinical effectivenss of various neurohormonal antagonists with outcomes in HF-PEF using propensity-matched designs that allow outcome-blinded assembly of balanced cohorts, a key feature of randomized clinical trials.