Erythropoietin (EPO) is the primary modulator of red blood cell production. Recently EPO has received considerable attention for its functions outside of hematopoiesis, including its effects in the nervous system where it has been shown to act as a neuroprotectant. To understand the function of EPO in the nervous system and to determine if EPO functions through the same signaling pathways identified in hematopoietic cells, we used cDNA array hybridization and RT-PCR to investigate the changes in gene expression induced by EPO in the neuronal-like PC-12 cell line. PC-12 cells cultured in the presence of EPO (10 U/ml) showed significant changes in gene expression by 3 h with a return to basal expression levels for the vast majority of genes by 24 h. The genes influenced by EPO included genes with known functions in cell proliferation, differentiation and apoptosis. Semi-quantitative RT-PCR confirmed that 24 h pre-treatment with EPO (10 pM) resulted in a 2.5-fold increase in the expression of the anti-apoptotic gene bcl(XL) and a 4-fold decrease in the expression of the pro-apoptotic gene bak. In addition to supporting the current models of EPO function these results suggest previously unidentified mechanisms by which EPO may function in neurons.