Permanent correction of gene defects is an appealing approach to the treatment of genetic disorders. The use of single-stranded oligodeoxynucleotides (ssODNs) has been demonstrated to induce single-point mutations in the dystrophin gene and to restore dystrophin expression in the skeletal muscle of models of Duchenne muscular dystrophy (DMD). Here we show that ssODNs made of peptide nucleic acids (PNA-ssODNs) can achieve gene repair frequencies more than 10-fold higher than those obtained using an older generation of targeting oligonucleotides. Correction was demonstrated in muscles cells isolated from mdx(5cv) mice and was stably inherited over time. Direct intramuscular injection of PNA-ssODNs targeting the mdx(5cv) mutation resulted in a significant increase in dystrophin-positive fibers when compared with muscles that received the ssODNs designed to correct the dystrophin gene but made of unmodified bases. Correction was demonstrated at both the mRNA and the DNA levels using quantitative PCR and was confirmed by direct sequencing of amplification products. Analysis at the protein level demonstrated expression of full-length dystrophin in vitro as well as in vivo. These results demonstrate that oligonucleotides promoting strand invasion in the DNA double helix can significantly enhance gene repair frequencies of the dystrophin gene. The use of PNA-ssODNs has important implications in terms of both efficacy and duration of the repair process in muscles and may have a role in advancing the treatment of DMD.