Background: The systemic immune-inflammation index (SII) is a proven, reliable inflammatory marker of the atherosclerotic process. Additionally, inflammation is one of the most important mechanisms of heart failure (HF) after myocardial infarction (MI). However, it is not clear whether SII is related to the risk of in-hospital HF in patients with MI. Thus, we aimed to explore the relationship between SII and the risk of new-onset in-hospital HF in ST-segment elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (pPCI). Methods: A total of 5586 patients with STEMI underwent pPCI at seven clinical sites in China from January 2015 to August 2021. The patients were divided into two groups based on the SII values. The association between SII and new-onset in-hospital HF in STEMI patients was assessed using logistic regression analysis. Results: Ultimately, 3808 STEMI patients with Killip class I who were treated with pPCI were included. All included patients were divided into two groups based on the calculated SII (Q1 SII: <1707.31 (x10(9)/L), Q2 SII: >= 1707.31 (x10(9)/L)). After unadjusted and multivariate adjustment for age, gender, vital signs, smoking, hypertension, diabetes mellitus, etc., the odds ratio (OR) of the in-hospital HF risk in Q2 was 1.378-1.427 times the Q1 in the calibration Models 1 to 5. Subgroup analysis showed that the OR of Q2 was 1.505-fold higher of Q1 in males and 1.525-fold in older people (>= 60 years). Sensitivity analysis showed that after excluding patients who had previously experienced HF, MI, or underwent PCI, elevated SII was still associated with a significant increase in the risk of in-hospital HF. Conclusions: Elevated SII is associated with an increased risk of in-hospital HF in STEMI patients treated with pPCI, particularly in male and older patients. Clinical Trial Registration: The Chinese STEMI pPCI Registry was registered with ClinicalTrials.gov (NCT04996901, https://www.clinicaltrials.gov/study/NCT04996901?cond=NCT04996901&rank=1).