Insulin-like growth factor I (IGF-I) is a potent regulator of oligodendrocyte development and myelination in vitro, but its effect on myelination in vivo has never been tested directly. Therefore, we examined brain growth and myelination in a transgenic mouse line that overexpresses IGF-I. By postnatal day 55, when brain growth and myelination are essentially complete in normal mice, the brains of transgenic mice were 55% larger than those of controls owing to an increase in cell size and apparently in cell number. Most or all brain structures appeared to be affected. At the same time, total myelin content of the transgenic mice was 130% greater than that of controls. Oligodendrocyte number as a percentage of total cell number was not increased in the transgenic mouse brains; the increase in myelin content was primarily the result of an increase in myelin production per oligodendrocyte. These findings indicate that IGF-I is a potent inducer of brain growth and myelination in vivo.