MicroRNAs (miRNAs) are noncoding RNAs that act as negative regulators of gene expression. Interestingly, specific alterations of miRNA expression have been found in failing hearts of different etiologies. The aim of this study was to identify the miRNA expression pattern of peripheral blood mononuclear cells (PBMCs) derived from chronic heart failure (CHF) patients affected by ischemic (ICM) and nonischemic dilated (NIDCM) cardiomyopathy. The expression profile of 257 miRNAs was assessed in 7 NIDCM patients, 8 ICM patients, and 9 control subjects by quantitative real-time PCR. Significantly modulated miRNAs were validated by using an independent set of 34 CHF patients (NIDCM = 19, ICM = 15) and 19 control subjects. Three miRNAs (miR-107, -139, and -142-5p) were downmodulated in both NIDCM and ICM patients versus control subjects. Other miRNAs were deregulated in only one of the CHF classes analyzed compared with control subjects: miR-142-3p and -29b were increased in NIDCM patients, while miR-125b and -497 were decreased in ICM patients. Bioinformatic analysis of miRNA predicted targets and of gene expression modifications associated with CHF in PBMCs indicated a significant impact of the miRNA signature on the transcriptome. Furthermore, miRNAs of both the NIDCM and the ICM signature shared predicted targets among CHF-modulated genes, suggesting potential additive or synergistic effects. The present study identified miRNAs specifically modulated in the PBMCs of NIDCM and ICM patients. Intriguingly, most of these miRNAs were previously reported as deregulated in human and/or mouse failing hearts. The identified miRNAs might have a potential diagnostic and/or prognostic use in CHF.