Fibroblast growth factor 2 (FGF-2) has a neurotrophic effect on dopaminergic neurons in vitro and in vivo, and exhibits beneficial effects in animal models of neurodegenerative disorders such as Parkinson's disease (PD). The poor stability and short half-life of FGF-2, however, have hampered its clinical use for neurological diseases. In the present study, we modified native recombinant human FGF-2 (rhFGF-2) by covalently attaching polyethylene glycol (PEG) polymers, named PEGylation, to enhance its neuroprotection efficacy in 6-hydroxydopamine (6-OHDA)-induced model of PD. In vitro, PEG-rhFGF-2 performed better biostability in 6-OHDA-induced PC-12 cells than native rhFGF-2. The in vivo data showed that, compared with native rhFGF-2, PEGylated rhFGF-2 was more efficacious in preventing 6-OHDA-induced lesion upon tyrosine hydroxylase-positive neurons in the substantia nigra (SN), improving the apomorphine-induced rotational behavior and the 6-OHDA-induced decline in tissue concentration of dopamine (DA) and its metabolites. Importantly, our data showed that the superior pharmacological activity of PEGylated rhFGF-2 is probably due to its greater permeability through the blood-brain barrier and better in vivo stability compared to native rhFGF-2. The enhanced stability and bioavailability of PEGylated rhFGF-2 make this molecule a great therapeutic candidate for neurodegenerative diseases such as PD and mood disorders.