Angiotensin Converting Enzyme (ACE) inhibitors are one of the recommended prevention therapy for patients with acute myocardial infarction (AMI) in the clinical guidelines. Two types (tissue and non-tissue) of ACE inhibitors are available with huge cost difference but the comparative treatment benefit and risk between them are unclear. The objective of this study was to investigate the comparative treatment effectiveness and safety between tissue and non-tissue ACE inhibitors among elderly patients after AMI. This is a retrospective cohort study with intention to treatment design using Medicare service claims files from 2007 to 2009 with Medicare beneficiaries 65 years or older after the index AMI hospitalization and who survived to discharge between January 1 2008 to December 31 2008 and received ACE inhibitors (N=34,679). Risk adjustment and instrumental variable (IV) analyses were used to investigate comparative treatment effectiveness including AMI, stroke, heart failure requiring hospitalization, all-cause mortality and a composite of the endpoints during the follow-up and the comparative treatment safety - a composite of hyperkalemia and acute renal failure requiring hospitalization during the follow-up. Both the risk adjustment and IV analyses showed no significant differences between tissue and non-tissue ACE inhibitors for the investigated outcomes of the comparative treatment effectiveness and safety in the study cohort. However, subgroup analyses from the IV models showed that tissue ACE inhibitors as compared to non-tissue ACE inhibitors increased the hazard risk by approximately 30% to 60% (p < 0.05) for heart failure requiring hospitalization among the patients with heart failure and reduced hazard risk by approximately 30% to 40% (p <0.05) for AMI among patients without heart failure. In conclusion, though this study did not find significant difference between tissue and non-tissue ACE inhibitors for the comparative treatment effectiveness and safety in the study cohort, considerable comparative treatment effectiveness may exist in the subgroup of patients with and without heart failure in the elderly patients after AMI.