Hyperglycemia that occurs under the diabetic condition is a major cause of diabetic complications such as diabetic neuropathy, one of the most common diabetes-related complications. It is well known that hyperglycemia could result in generation of reactive oxygen species (ROS). Over production of ROS recommended as an important mediator for apoptotic signaling pathway as well as a key early event in the development of diabetic neuropathy. Recently, many studies have indicated that lithium has robust neuroprotective effect in relation to several neurodegenerative diseases. The present study aimed to examine effects of lithium on high glucose (HG)-induced neurotoxicity and to determine some of the underlying molecular mechanisms involved in this response in PC12 cells as a neuronal culture model for diabetic neuropathy. PC12 cells were pretreated with different concentrations of lithium for 7 days, exposed to HG for 24 h. Cell viability was measured by MTT assay. ROS and lipid peroxidation levels as well as superoxide dismutase activity were measured. In order to examine the underlying molecular mechanisms, the expressions of Bax, Bcl-2, Caspase-3, total and phosphorylated JNK and P38 MAPK were also analyzed by Western blotting. The present results indicated that pretreatment with 1 mM lithium has protected PC12 cells against HG-induced apoptotic cell death. It could reduce ROS generation, Bax/Bcl-2 ratio, Caspase-3 activation, and JNK and P38 MAPK phosphorylation. It may be concluded that in HG condition, lithium pretreatment could prevent mitochondrial apoptosis as well as JNK and P38 MAPK pathway in PC12 cells.