This study investigated the effect of ferulic acid (FA) on the up-regulation of heme oxygenase-1 (HO-1) in lymphocytes and the molecular mechanisms involved. Lymphocytes were treated with FA (0.001-0.1 μM) for certain times. Cell viability, the activity and level of expression of HO-1, and signal pathways were analyzed. FA significantly upregulated HO-1 expression both at the level of mRNA and protein in lymphocytes. Moreover, FA induced NF-E2-related factor (Nrf2) nuclear translocation and transcriptional activity, which is upstream of FA induced HO-1 expression. In addition, lymphocytes treated with FA exhibited activation of extracellular regulated kinase (ERK) and treatments with U0126 (an ERK kinase inhibitor) attenuated the FA induced activation of Nrf2, resulting in a decrease in HO-1 expression. Zinc protoporphyrin (ZnPP, a HO-1 inhibitor) markedly suppressed cytoprotection from radiation-induced cell damage by FA. Results suggested that the ERK signaling pathway controlled the anti-oxidation of FA by regulating the expression of the antioxidant enzyme HO-1.