The transforming growth factor-betas (TGF-βs) regulate the induction of dopaminergic neurons and are elevated in the CSF of Parkinson's patients. We report here that mice with TGF-β2 haploinsufficiency (TGF-β2 +/−) have subclinical defects in the dopaminergic neurons of their substantia nigra pars compacta. At 6 weeks of age, the TGF-β2 +/− mice had 12% fewer dopaminergic neurons than wild-type littermates. No additional loss of neurons occurred during the next 5 months, although striatal dopamine declined to 70% of normal. The level of 3,4-dihydroxphenylacetic acid was normal in the TGF-β2 +/− mice, indicating that a compensatory mechanism maintains dopamine stimulation of their striatum. The TGF-β2 +/− mice had normal sensitivity to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tretrahydropyridine, despite having reduced levels of monoamine oxidase-B. These results raise the possibility that people with naturally low levels of TGF-β2 may have less functional reserve in their nigrostriatal pathway, causing them to be at increased risk of developing Parkinson disease.