Our groups have reported that tumor necrosis factor-α (TNF-α) causes myelin damage and apoptosis of oligodendrocytes and their precursors in vitro and in vivo. We also have reported that insulin-like growth factor-I (IGF-I) can protect cultured oligodendrocytes and their precursors from TNF-α-induced damage. In this study, we investigated whether IGF-I can protect oligodendrocytes and myelination from TNF-α-induced damage in vivo by cross-breeding TNF-α transgenic (Tg) mice with IGF-I Tg mice that overexpress IGF-I exclusively in brain. At 8 weeks of age, compared with those of wild-type (WT) mice, the brain weights of TNF-α Tg mice were decreased by ∼20%, and those of IGF-I Tg mice were increased by ∼20%. The brain weights of mice that carry both TNF-α and IGF-I transgenes (TNF-α/IGF-I Tg mice) did not differ from those of WT mice. As judged by histochemical staining and immunostaining, myelin content in the cerebellum of TNF-α/IGF-I Tg mice was similar to that in WT mice and much more than that in TNF-α Tg mice. Consistently, Western immunoblot analysis showed that myelin basic protein (MBP) abundance in the cerebellum of TNF-α/IGF-I Tg mice was double that in TNF-α Tg mice. In comparison with WT mice, the number of oligodendrocytes was decreased by ∼36% in TNF-α Tg mice, whereas it was increased in IGF-I Tg mice by ∼40%. Oligodendrocyte number in TNF-α/IGF-I Tg mice was almost twice that in TNF-α Tg mice. Furthermore, IGF-I overexpression significantly reduced TNF-α-induced increases in apoptotic cell number, active caspase-3 abundance, and degradaion of MBP. Our results indicate that IGF-I is capable of protecting myelin and oligodendrocytes from TNF-α-induced damage in vivo. © 2007 Wiley-Liss, Inc.