Heart failure (HF) occurs when disease or injury weakens the heart muscle and its ability to pump blood effectively. Current HF treatment paradigms are based on symptom and LV dysfunction severity, with little regard to etiology, reflecting a lack of knowledge of underlying HF mechanisms and highlighting a critical barrier to more effective treatments. We used RNA-seq and pathway analysis in 64 explanted LV human heart tissues to identify transcriptome signatures common to HF with reduced EF and unique to specific HF etiologies. We identified differentially expressed genes (DEGs) between dilated cardiomyopathy (DCM, n = 37) and non-failing controls (NF, n = 14) and between ischemic cardiomyopathy (ICM, n = 13) and NF. Between DCM and NF, there were 3,649 DEGs, and between ICM and NF, there were 4,150 DEGs (FDR ≤ 5%). These comparisons share 2,691 DEGs, all with fold-changes in the same direction for both comparisons, representing the expression signature common to HF with reduced EF. Using Ingenuity Pathway Analysis (IPA), these DEGs are enriched for pathways suggesting dysregulation of energy metabolism (Mitochondrial Dysfunction, p = 5e-16; Oxidative Phosphorylation, p = 2e-14) and apoptosis (Protein Ubiquitination, p = 1e-11). There are 688 DCM-specific genes and 1,189 ICM-specific genes. Using unsupervised hierarchical clustering, expression of these 1,877 genes clusters the samples into diseases. Pathway analysis at p ≤ 0.003 demonstrates the majority of pathways are disease-specific, with DCM and ICM sharing only two. DCM-specific genes are enriched for pathways suggesting dysfunctional cell-cell adhesion (Germ Cell-Sertoli Cell Junction Signaling) and detoxification (NRF2-mediated Oxidative Stress Response). ICM-specific pathways are enriched for cytoskeletal (Signaling by Rho Family GTPases, Actin Cytoskeleton, Integrin, Epithelial Adherens Junction, Rac) and immune system pathways (Antigen Presentation Pathway, CD40, CD28 in T Helper Cells, JAK/Stat, IL-8, and IL-6), suggesting an immune response and fibrosis of damaged tissue. Our results demonstrate the commonalities of HF pathways as well as disease-specific signatures in DCM and ICM that could potentially aid in development of future precision medicine treatments.