Background Secondary prevention medications are often not prescribed to frail, older adults following acute myocardial infarction, potentially because of the absence of data to support use, perceived lack of benefit, and concern over possible harms. We examined the effect of using more guideline-recommended medications after myocardial infarction on mortality, rehospitalization, and functional decline in the frailest and oldest segment of the US population-long-stay nursing home residents. Methods and Results We conducted a retrospective cohort study of nursing home residents aged ≥65 years using 2007 to 2010 national US Minimum Data Set clinical assessment data and Medicare claims. Exposure was the number of secondary prevention medications (antiplatelets, β-blockers, statins, and renin-angiotensin-aldosterone system inhibitors) initiated after myocardial infarction. Outcomes were 90-day death, rehospitalization, and functional decline. We compared outcomes for new users of 2 versus 1 and 3 or 4 versus 1 medications using the inverse probability of treatment-weighted odds ratios with 95% CI. The cohort comprised 4787 residents, with a total of 509 death, 820 functional decline, and 1226 rehospitalization events. Compared with individuals who initiated 1 medication, mortality odds ratios were 0.98 (95% CI, 0.79-1.22) and 0.74 (95% CI, 0.57-0.97) for users of 2 and 3 or 4 medications, respectively. Rehospitalization odds ratios were 1.00 (95% CI, 0.85-1.17) for 2 and 0.97 (95% CI, 0.8-1.17) for 3 or 4 medications. Functional decline odds ratios were 1.04 (95% CI, 0.85-1.28) for 2 and 1.12 (95% CI, 0.89-1.40) for 3 or 4 medications. In a stability analysis excluding antiplatelet drugs from the exposure definition, more medication use was associated with functional decline. Conclusions Use of more guideline-recommended medications after myocardial infarction was associated with decreased mortality in older, predominantly frail adults, but no difference in rehospitalization. Results for functional decline from the main and stability analyses were discordant and did not rule out an increased risk associated with more medication use.