PURPOSE: To investigate whether zeaxanthin, the predominant carotenoid pigment of the macular pigments in human retina, provides neuroprotection against retinal cell damage. METHODS: We used in vitro cultured retinal ganglion cells (RGCs), specifically RGC-5, an E1A virus-transformed rat cell line. Cell damage was induced either by a 24-hr exposure to hydrogen peroxide (H2O2) or by serum deprivation. Cell viability was measured using the tetrazolium salt, WST-8. The scavenging capacity of zeaxanthin for H2O2, superoxide anion radical (O2.-), and hydroxyl radical (HO.) was measured using a radical scavenging capacity assay with CM-H2DCFDA, a reactive oxygen species (ROS)-sensitive probe. RESULTS: When added to RGC-5 cell cultures, 0.1, 10, and 1 microM zeaxanthin scavenged the free radicals induced by H2O2, O2.-, and HO., respectively. In addition, pretreatment with 1 microM zeaxanthin permitted scavenging of staurosporine-induced intracellular radicals. Zeaxanthin also inhibited the neurotoxicity induced by H2O2 or serum deprivation and scavenged the intracellular radicals induced by H2O2 or serum deprivation. CONCLUSIONS: Our results suggest that zeaxanthin provides effective protection against oxidative stress-induced retinal cell damage.