Slowing or halting the progressive dopaminergic (DA) degeneration in Parkinson's disease (PD) would delay the onset and development of motor symptoms, prolong the efficacy of pharmacotherapies and decrease drug-induced side-effects. We tested the potential of two orally administered novel immunophilin ligands to protect against DA degeneration in two animal models of PD. First, in an MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model, we compared an immunophilin ligand (V-10,367) documented to bind the immunophilin FKBP12 with V-13,661, which does not bind FKBP12. Both molecules could prevent the loss of striatal DA innervation in a dose-dependent fashion during 10 days of oral administration. Second, to determine whether an immunophilin ligand can protect against progressive and slow DA degeneration typical of PD, an intrastriatal 6-hydroxydopamine-infusion rat model was utilized. Oral treatment with the FKBP12-binding immunophilin ligand began on the day of lesion and continued for 21 days. At this time point, post mortem analyses revealed that the treatment had prevented the progressive loss of DA innervation within the striatum and loss of DA neurons within the substantia nigra, related to functional outcome as measured by rotational behaviour. Notably, DA fibres extending into the area of striatal DA denervation were observed only in rats treated with the immunophilin ligand, indicating neuroprotection or sprouting of spared DA fibres. This is the first demonstration that immunophilin ligands can prevent a slow and progressive DA axonal degeneration and neuronal death in vivo. The effects of orally administered structurally related immunophilin ligands in acute and progressive models of DA degeneration are consistent with the idea that these compounds may have therapeutic value in PD.