Excitation-contraction coupling (ECC) is impaired in muscles of mdx mice, an animal model of Duchenne muscular dystrophy (DMD). Insulin-like growth factor-I (IGF-I) has therapeutic potential for DMD, and has been shown to enhance skeletal muscle dihydropyridine receptor function and gene expression. We tested the hypothesis that muscle specific overexpression of IGF-I in mdx mice (mIGF-I-mdx) improves ECC. Mechanically skinned fibres were prepared from EDL muscles excised from C57BL/10, mdx, and mIGF-I-mdx mice that were anaesthetised with pentobarbital sodium (60 mg/kg, i.p.). The mice were then killed by cardiac excision. The number of depolarization-induced contractions (DICR) before reaching a 50% reduction in DICR amplitude, was lower in fibres from mdx (7 ± 1, n = 15 fibres) than C57BL/10 mice (16 ± 2, n = 12 fibres), but there was no difference in SR Ca2+ loading or Ca2+ leak rates. In mIGF-I-mdx mice, rundown of DICR was improved significantly compared to mdx mice (14 ± 2 depolarizations, n = 14 fibres, P < 0.05). There was no change in SR Ca2+ loading, but the amount of releasable SR Ca2+ was increased, possibly due to the reduction in Ca2+ leak rate (mdx: 19 ± 3% reduction, n = 13 vs mIGF-I-mdx: 7 ± 3% reduction, n = 14). The results support the hypothesis that muscle specific overexpression of IGF-I improves ECC in mdx mice.