Parkinson's disease (PD) is a progressive neurodegenerative disorder with selective loss of dopaminergic neurons in the substantia nigra. Evidence suggests that oxidative stress is involved in the pathogenesis of PD. Sulforaphane (SF), a naturally occurring isothiocyanate, has been shown to protect against oxidative stress by inducing the expression of various NF-E2-related factor-2 (Nrf2) responsive genes. Previous studies have shown that SF protects dopaminergic neurons against PD-related neurotoxin 6-hydroxydopamine (6-OHDA)-induced cytotoxicity. However, the molecular mechanisms by which SF protects against 6-OH DA-induced cytotoxicity are poorly elucidated. In this study, we found that pretreatment with SF significantly reduced 6-0HD-Ainduced caspase-3 activation and subsequent cell death. SF also increased heme oxygenase-I (HO-1) expression, which conferred protection against 6-OH DA-induced cytotoxicity. Furthermore, SF induced the translocation of Nrf2 into the nucleus and activated PI3K/Akt, a pathway that is involved in SF-induced Nrf2 nuclear translocation, HO-1 expression and cytoprotection. These results suggest that SF inhibits 6-OHDA-induced cytotoxicity through increasing HO-1 expression in a PI3K/Akt-dependent manner.