Clinically, the differentiation between ischemic (ICM) and non-ischemic (NICM) human cardiomyopathies is highly relevant, as ICM and NICM differ with respect to prognosis and certain aspects of pharmacological therapy, despite a common final phenotype characterized by ventricular dilatation and reduced contractility. So far, it is unclear whether microarray-based signatures can be used to infer the etiology of heart failure. Using three different classification algorithms, we independently analyzed one cDNA- and two publicly available high-density oligonucleotide microarray studies comprising a total of 279 end-stage human heart failure samples. When classifiers identified in a single study where applied to the remaining studies, misclassification rates >25% for ICM and NICM specimens were noted, indicating poor separation of both etiologies. However, data mining of 458 classifier genes that were concordantly identified in at least two of the three datasets, points to different biological processes in ICM vs. NICM. Consistent with the underlying ischemia, cytokine signaling pathways and immediate early response genes were overrepresented in ICM samples, whereas NICM samples displayed a deregulation of cytoskeletal transcripts, genes encoding for the major histocompatibility complex, and antigen processing and presentation pathways, potentially pointing to immunologic processes in NICM. Overall, our results suggest that ischemic and non-ischemic cardiomyopathies exhibit substantial heterogeneity at the transcriptomic level. Prospective studies are required to test whether etiology-specific gene expression patterns are present at earlier disease stages or in subsets of both etiologies.