Background: Aluminum (Al) exposure is among the environmental risk factors that may involve in the pathogenesis of neurodegenerative diseases. Oxidative stress has a critical role in the Al-induced toxicity. Saffron is a plant with potent radical scavenging and anti-oxidative properties. This investigation was designed to evaluate the possible protective effects of saffron extract (SE) on aluminum maltolate (Almal)-induced oxidative stress and apoptosis in PC12 cell line.Methods: In this in vitro study, PC12 cells were divided into four groups including control, Almal (500 µM), Almal+SE (50 μg/ml), and Almal+SE (100 μg/ml). After 48 hours of treatment with Almal in the absence and presence of SE, cell viability and apoptosis were determined using MTT (3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide) assay and Annexin V flow cytometry, respectively. Catalase activity was determined as an index of oxidative stress. Statistical analyses were performed using one-way ANOVA (SPSS version 16.0). P<0.05 was accepted as a statistically significant difference between groups.Results: Almal decreased the PC12 cells viability dose-dependently (IC50=500µM). Co-treatment of 50 and 100 μg/ml of SE with 500 µM of Al increased cell viability to 79% (P=0.04) and 86% (P=0.02) of the control group, respectively. Al also increased PC12 cells apoptosis and catalase activity to 37 and 2.7 folds of those of the control group (P<0.001 and =0.001respectively). 100 μg/ml of SE blunted the effects of Al on the increased cell apoptosis (P=0.02) and changes in the catalase activity (P=0.003).Conclusion: SE has protective effects against Al-induced apoptosis and oxidative stress and may possess therapeutic values in the treatment of Al-neurotoxicity.