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Background: Inflammation is essential in cardiovascular disease (CVD) development and progression. A novel inflammatory parameter, the systemic inflammation response index (SIRI), has been proven to predict cancer prognosis strongly. Little is known about the relationship between SIRI and outcomes in patients with ST-segment elevation myocardial infarction (STEMI). Methods: 1312 STEMI patients who underwent percutaneous coronary intervention (PCI) in Beijing Anzhen hospital from January 2019 to December 2021 were analyzed. SIRI was calculated as neutrophils × monocytes/lymphocytes. Our primary outcome was a 30-day major adverse event (MACE), including all-cause mortality, non-fatal myocardial infarction (MI), stroke, incident heart failure (HF), cardiogenic shock, and cardiac arrest. Results: Patients were stratified into four groups according to quartiles of SIRI: SIRI <1.58 (n = 328), 1.58≤ SIRI <3.28 (n = 328), 3.28≤ SIRI <7.80 (n = 328), SIRI ≥7.80 (n = 328). Higher SIRI was associated with a higher incidence of the 30-day MACE. The rates of 30-day MACE were 6.1%, 8.8%, 12.8%, and 17.1% (p < 0.001) for the lowest SIRI quartile to the highest quartile, respectively. This association was consistent in the outcome of HF but no other components. Higher SIRI indicated higher 30-day MACE incidence in most participants except in those with very high inflammatory indicators. Subgroup analysis showed this correlation was consistent in various subgroups (p for interaction >0.05). Conclusions: In patients with STEMI, higher SIRI indicated a higher incidence of 30-day MACE, except for those with very high inflammatory indicators. In most STEMI patients, SIRI might be a trustworthy indicator of short-term prognosis.