AbstractInsulin-like growth factor-I (IGF-I) is involved in the maturation and maintenance of neurons, and impaired IGF-I signaling has been shown to play a role in various neurological diseases including stroke. The aim of the present study was to investigate the efficacy of an optimized IGF-I variant by adding a 40 kDa polyethylene glycol (PEG) chain to IGF-I to form PEG-IGF-I. We show that PEG-IGF-I has a slower clearance which allows for twice-weekly dosing to maintain steady-state serum levels in mice. Using a photothrombotic model of focal stroke, dosing from 3 hrs post-stroke dose-dependently (0.3–1 mg/kg) decreases the volume of infarction and improves motor behavioural function in both young 3-month and aged 22–24 month old mice. Further, PEG-IGF-I treatment increases GFAP expression when given early (3 hrs post-stroke), increases Synaptophysin expression and increases neurogenesis in young and aged. Finally, neurons (P5–6) cultured in vitro on reactive astrocytes in the presence of PEG-IGF-I showed an increase in neurite length, indicating that PEG-IGF-I can aid in sprouting of new connections. This data suggests a modulatory role of IGF-I in both protective and regenerative processes, and indicates that therapeutic approaches using PEG-IGF-I should be given early and where the endogenous regenerative potential is still high.