Introduction: Systemic Immune-inflammation Index (SII) is a novel marker of inflammation, used extensively in prognosticating various cancers. Recent studies have shown SII to be a predictor of adverse events and death in Acute Coronary Syndrome (ACS) patients who undergo intervention. The role of SII in medically managed SII patients has not been studied. There are no Indian studies available which study the prognosticative role of SII in ACS. Aim: To study systemic immune-inflammation index in acute coronary syndrome and its role in predicting disease severity and mortality. Materials and Methods: This prospective cohort study was conducted in Department of General Medicine at Father Muller Medical College Hospital, Mangaluru, India between February 2021 and July 2021. The study included 45 ST Elevation Myocardial Infarction (STEMI) and 45 Non ST Elevation Myocardial Infarction (NSTEMI)/Unstable Angina (UA) patients, aged 30 years or more. The SII, Neutrophil-to-Lymphocyte Ratio (NLR) and Total Leucocyte Count (TLC) were compared using independent sample t-test. Killip class, Thrombolysis In Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) 2.0 scores were used to determine disease severity. Pearson’s and Spearman’s correlation coefficient were used to determine correlation between parametric and non parametric parameters, respectively. Receiver Operator Curve (ROC) was used to see for predictability of outcomes. The role of SII to predict Major Adverse Cardiac Events (MACE) and death at one month follow- up period was assessed by Kaplan-Meier analysis and Cox regression analysis. Results: The mean SII was significantly higher in the STEMI group (20.9 vs 9.79; t-value= 3.65, p-value <0.001). SII correlated significantly with Killip class (r=0.502), TIMI (r=0.417) and GRACE 2.0 scores (r=0.529), better than NLR or TLC. High SII were associated with a higher risk of MACE (Odds ratio=13.82, p-value <0.001) and death (OR=4.413, p-value=0.015). The SII had an Area Under the Curve of 0.67 for predicting MACE and had a negative predictive value of 96%. Kaplan-Meier analysis showed that patients with higher SII had a lower survival at one month (median: 24.5 days vs 29.32 days, Log-rank=6.44, p-value=0.011). The SII predicted MACE and death better than left ventricular Ejection Fraction (EF) and troponin I. Conclusion: The SII is a cost-effective, novel marker of inflammation that can predict short term outcomes in ACS. This was the first cohort study which studied the role of SII in ACS in patients undergoing any type of intervention.