Barth Syndrome (BTHS) is an early onset, lethal X-linked disorder caused by a mutation in tafazzin (TAFAZZIN), a mitochondrial acyltransferase that remodels monolysocardiolipin (MLCL) to mature cardiolipin (CL) and is essential for normal mitochondrial, cardiac, and skeletal muscle function. Current gene therapies in preclinical development require high levels of transduction. We tested whether TAFAZZIN gene therapy could be enhanced with the addition of a cell-penetrating peptide, penetratin (Antp). We found that TAFAZZIN-Antp was more effective than TAFAZZIN at preventing the development of pathological cardiac hypertrophy and heart failure. These findings indicate that a cell-penetrating peptide enhances gene therapy for BTHS.