Over expression of heme oxygenase-1 (HO-1) was observed in both astroglia and neurons in the substantia nigra pars compacta of patients with Parkinson’s disease (PD). However, the role of HO-1 in PD pathogenesis remains unknown. To determine whether and how HO-1 participates differentially in astroglia and neurons vulnerability, we first analyzed time-dependent HO-1 expression induced by 1-methyl-4-phenyl-pyridinium (MPP+) and alpha-synuclein in primary cultured mesencephalic astroglia and neurons. The results showed that both toxins induced a time-dependent HO-1 up-regulation in these cells, however, neuronal HO-1 up-regulation appeared much later than glial. We further demonstrated that HO-1 inhibitor zinc protoporphyrin aggravated MPP+ induced oxidative damage in both astrocytes and neurons, indicating this HO-1 response was cyto-protective. Overexpression of HO-1 induced by activator cobalt protoporphyrin (copp) showed protective effects on neurons in the time of inadequate HO-1 up-regulation, however, aggragates MPP+ induced oxidative damage at the peak of HO-1 response. For astroglia, copp always showed dose-dependent protective effects. These results indicate that between astrogila and neurons, HO-1 was differentially modulated in a time-dependent manner and over-expressed HO-1 might play different roles in cellular antioxidation.