Importance: Wide heterogeneity exists in acute myocardial infarction treatment and outcomes in India. Objective: To evaluate the effect of a locally adapted quality improvement tool kit on clinical outcomes and process measures in Kerala, a southern Indian state. Design, Setting, and Participants: Cluster randomized, stepped-wedge clinical trial conducted between November 10, 2014, and November 9, 2016, in 63 hospitals in Kerala, India, with a last date of follow-up of December 31, 2016. During 5 predefined steps over the study period, hospitals were randomly selected to move in a 1-way crossover from the control group to the intervention group. Consecutively presenting patients with acute myocardial infarction were offered participation. Interventions: Hospitals provided either usual care (control group; n = 10 066 participants [step 0: n = 2915; step 1: n = 2649; step 2: n = 2251; step 3: n = 1422; step 4; n = 829; step 5: n = 0]) or care using a quality improvement tool kit (intervention group; n = 11 308 participants [step 0: n = 0; step 1: n = 662; step 2: n = 1265; step 3: n = 2432; step 4: n = 3214; step 5: n = 3735]) that consisted of audit and feedback, checklists, patient education materials, and linkage to emergency cardiovascular care and quality improvement training. Main Outcomes and Measures: The primary outcome was the composite of all-cause death, reinfarction, stroke, or major bleeding using standardized definitions at 30 days. Secondary outcomes included the primary outcome{\textquoteright}s individual components, 30-day cardiovascular death, medication use, and tobacco cessation counseling. Mixed-effects logistic regression models were used to account for clustering and temporal trends. Results: Among 21 374 eligible randomized participants (mean age, 60.6 [SD, 12.0] years; n = 16 183 men [76\%] ; n = 13 689 [64\%] with ST-segment elevation myocardial infarction), 21 079 (99\%) completed the trial. The primary composite outcome was observed in 5.3\% of the intervention participants and 6.4\% of the control participants. The observed difference in 30-day major adverse cardiovascular event rates between the groups was not statistically significant after adjustment (adjusted risk difference, -0.09\% [95\% CI, -1.32\% to 1.14\%]; adjusted odds ratio, 0.98 [95\% CI, 0.80-1.21]). The intervention group had a higher rate of medication use including reperfusion but no effect on tobacco cessation counseling. There were no unexpected adverse events reported. Conclusions and Relevance: Among patients with acute myocardial infarction in Kerala, India, use of a quality improvement intervention compared with usual care did not decrease a composite of 30-day major adverse cardiovascular events. Further research is needed to understand the lack of efficacy. Trial Registration: clinicaltrials.gov Identifier: NCT02256657.