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Background: Heart failure (HF) is a major medical, and epidemiological problems with ischemic heart disease (IHD) is the most common cause of HF. We aimed to assess the plasma B-type natriuretic peptide (BNP) levels, serum growth differentiation factor 15 (GDF15), and high-sensitivity troponin I (hsTnI) in HF patients with and without IHD., Methods: The study included 120 HF patients, categorized into 51 patients with IHD and 69 patients without apparent IHD. Clinical and echocardiographic assessments of the included patients were performed. ELISA assays of plasma BNP and serum GDF15 were done, while serum hsTnI was measured using chemiluminescent immunoassay., Results: There were significantly higher median values of serum levels for GDF15 (pg/mL) and hsTnI (pg/mL) among IHD group (1,630.5 and 141.8, respectively) compared to non-IHD group (895 and 14.3, respectively, p ˂ 0.05 for both), with non-significant differences regarding to the BNP plasma levels (p ˃ 0.05). In the IHD group, significant positive correlations were observed between GDF15 with both BNP (r = 0.655, p = < 0.001) and hsTnI (r = 0.496, p = < 0.001). Serum GDF15 at a cutoff of ≤ 717 pg/mL has the highest specificity [85.51% vs. 50.72% for BNP (at cutoff > 264 pg/mL) and 59.42% for hsTnI]. Additionally, hsTnI at a cutoff of > 45.2 pg/mL has the highest sensitivity (70.59% vs. 68.63% for BNP and 33.33% for GDF15) in discriminating heart failure with IHD from heart failure without IHD., Conclusions: A multimarker approach, particularly GDF15 and hsTnI, is helpful in identifying HF patients with underlying IHD, thus enabling their proper management.