AbstractPhysical exercise enhances adult neurogenesis in the hippocampus. Running induces the uptake of blood insulin‐like growth factor‐I (IGF‐I) into the brain. A causal link between these two phenomena has been reported; running‐induced increases in adult neurogenesis can be blocked by peripheral infusion of anti‐IGF‐I. Running also alters other aspects of hippocampal structure, including dendritic spine density. It remains unclear, however, whether these effects are also mediated through an IGF‐I mechanism. To examine this possibility, we blocked peripheral IGF‐I and examined adult neurogenesis and dendritic spine density in treadmill running mice. Two weeks of running resulted in an increase in cell proliferation in the dentate gyrus (DG) as well as an increase in dendritic spine density on DG granule cells and basal dendrites of CA1 pyramidal neurons, while having no effect on apical or basal dendritic spine density of CA3 pyramidal neurons. IGF‐I blockade reduced cell proliferation in both sedentary and running mice, but by contrast, this treatment had no effect on granule cell or CA3 pyramidal cell dendritic spine density in sedentary or running mice. However, IGF‐I antibody treatment seemed to prevent the running‐induced increase in spine density on basal dendrites of CA1 pyramidal cells. These results suggest that IGF‐I exerts a complex influence over hippocampal structure and that its effects are not restricted to those induced by running. © 2009 Wiley‐Liss, Inc.