Background— When β-blockers produce reverse-remodeling in idiopathic dilated cardiomyopathy, they partially reverse changes in fetal–adult/contractile protein, natriuretic peptide, SR-Ca ²⁺ -ATPase gene program constituents. The objective of the current study was to further test the hypothesis that reverse-remodeling is associated with favorable changes in myocardial gene expression by measuring additional contractile, signaling, and metabolic genes that exhibit a fetal/adult expression predominance, are thyroid hormone-responsive, and are regulated by β ₁ -adrenergic receptor signaling. A secondary objective was to identify which of these putative regulatory networks is most closely associated with observed changes. Methods and Results— Forty-seven patients with idiopathic dilated cardiomyopathy (left ventricular ejection fraction, 0.24±0.09) were randomized to the adrenergic-receptor blockers metoprolol (β _1- selective), metoprolol+doxazosin (β ₁ /α ₁ ), or carvedilol (β ₁ /β ₂ /α ₁ ). Serial radionuclide ventriculography and endomyocardial biopsies were performed at baseline, 3, and 12 months. Expression of 50 mRNA gene products was measured by quantitative polymerase chain reaction. Thirty-one patients achieved left ventricular ejection fraction reverse-remodeling response defined as improvement by ≥0.08 at 12 months or by ≥0.05 at 3 months (Δ left ventricular ejection fraction, 0.21±0.10). Changes in gene expression in responders versus nonresponders were decreases in NPPA and NPPB and increases in MYH6 , ATP2A2 , PLN , RYR2 , ADRA1A , ADRB1 , MYL3 , PDFKM , PDHX , and CPT1B . All except PDHX involved increase in adult or decrease in fetal cardiac genes, but 100% were concordant with changes predicted by inhibition of β ₁ -adrenergic signaling. Conclusions— In addition to known gene expression changes, additional calcium-handling, sarcomeric, adrenergic signaling, and metabolic genes were associated with reverse-remodeling. The pattern suggests a fetal–adult paradigm but may be because of reversal of gene expression controlled by a β ₁ -adrenergic receptor gene network. Clinical Trial Registration— URL: www.clinicaltrials.gov . Unique Identifier: NCT01798992.