Non-viral gene transfer into skeletal muscle is enhanced by electroporation and myotoxin preconditioning of muscle following plasmid injection. We investigated in vivo delivery of naked DNA to mdx mouse muscle, utilising enhanced green fluorescent protein reporter vector (pEGFP) and a corrective nucleic acid to promote targeted corrective gene conversion at the mutant mdx mouse dystrophin (DMDmdx) locus. Electroporation, myoablation with bupivacaine and a combined protocol, were applied to mdx muscle. We report up to 90% EGFP expression in electroporated mdx tibialis anterior muscle. Muscles preconditioned with bupivacaine showed low transgene expression with or without EP. Single EGFP+ve muscle fibre explants showed EGFP expression in mature fibres in preference to satellite cells. We observed a two-fold increase (P<0.005; t) in dystrophin protein, accompanied by wild-type (wt) DMD transcript in muscles injected with corrective nucleic acid over contralateral saline-injected TAs. By targeting the muscle fibres in preference to the satellite cells, plasmid-bourne transgenes delivered to dystrophic muscle will not penetrate the regenerative component of muscle. Whether in the context of targeted corrective gene conversion or therapeutic non-viral transgenes, under these conditions periodic re-administration will be required to promote phenotypic benefits in dystrophic muscle. © 2005 Elsevier B.V. All rights reserved.