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Background Differentiating type 1 myocardial infarctions (T1MI) from type 2 myocardial infarctions (T2MI) can be challenging based on clinical variables alone. This review aimed to explore the utility of novel and traditional biomarkers to discriminate between these entities and potentially provide additional prognostic information.Methods A systematic review of observational studies and randomised controlled trials that examined the discriminatory or prognostic roles of either traditional cardiac biomarkers (troponin, creatine kinase or b-type natriuretic peptide) or non-traditional biomarkers. Data sources included PubMed, SCOPUS, Web of Science, EMBASE and clinicaltrials.gov and were last searched on 15 November 2024. The diagnostic accuracy of biomarkers and prognostic utility of identified biomarkers are narratively reported.Results 31 studies with 16 111 individuals with a T2MI were included. Most studies (97%) demonstrated moderate or severe risk of bias. Of studies that examined traditional cardiac biomarkers (n=13), the ability to discriminate between T2MI and T1MI ranged from an area under the curve (AUC) of 0.61–0.71. Studies that added traditional cardiac biomarkers to clinical variables (n=4) demonstrated a diagnostic accuracy AUC 0.71–0.82. Studies exploring non-traditional biomarkers, metabolic and proteomic profiles (n=14) demonstrated a wide range of diagnostic accuracy (AUC 0.50–0.77). Traditional cardiac biomarkers inconsistently demonstrated a correlation with subsequent cardiovascular events. The prognostic utility of non-traditional biomarkers was infrequently assessed.Conclusion The role of biomarkers, metabolic and proteomic profiles in the diagnosis and prognostication of T2MI remains unclear. Higher quality studies and refining the classification of T2MI may improve this further.PROSPERO registration number CRD42023418095.