Sleep and circadian rhythm disruptions are frequent comorbidities of Parkinson's disease (PD), a disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. Although sleep/circadian disturbances can be observed years before diagnosing PD, it remains unclear whether circadian clocks have a causal role in the degenerative process. We demonstrated here that circadian clocks regulate the rhythmicity and magnitude of the vulnerability of DA neurons to oxidative stress in Drosophila. Circadian pacemaker neurons are presynaptic to a subset of DA neurons and rhythmically modulate their susceptibility to degeneration. The arrhythmic period (per) gene null mutation exacerbates the age-dependent loss of DA neurons and, in combination with brief oxidative stress, causes premature animal death. These findings suggest that circadian clock disruption promotes dopaminergic neurodegeneration.