Purpose: Oxidative stress and systemic inflammation are associated with chronic psychological stress, and play a major role in stress-induced neural atrophy. There is a wide body of literature linking oxidative and inflammatory stress with a reduction in both neurotrophic factors and psychological stress resilience. We investigated the potential for the dietary carotenoids lutein, zeaxanthin, and mesozeaxanthin (collectively the macular carotenoids [MC]), which have high antioxidant / anti-inflammatory capacity, to reduce psychological stress, serum cortisol, and the pro-inflammatory cytokines TNF-, IL-6, and IL-1. Levels of brain-derived neurotrophic factor (BDNF associated with neural plasticity) and behavioral data regarding emotional and physical well-being were also obtained.Methods: 59 young (18-25 yrs.), healthy subjects participated in a double-blind, placebo-controlled supplementation trial. Subjects were randomly assigned to one of three groups: placebo, 13 mg, or 27 mg / day total MCs. Fasting blood draws were conducted between 9-11 am. Serum cortisol, BDNF, TNF-, IL-6, IL-1, and serum antioxidant potential (AOP) were assessed via ELISA. The retinal concentration of MCs (termed macular pigment optical density [MPOD]) was determined via customized heterochromatic flicker photometry. Behavioral data were obtained via questionnaire. Results: Supplementation with MCs reduced psychological stress, serum cortisol, and measures of suboptimal emotional and physical health (p < 0.05 for all), versus placebo. BDNF, MPOD, and AOP all increased significantly versus placebo in both treatment groups as well (p < 0.05 for all). IL1- decreased significantly versus placebo in the treatment groups (p < 0.05). No significant changes in any parameter were found for the placebo group.Conclusions: Supplementation with the MCs had several significant effects, including reductions in psychological stress, cortisol, IL1-, and symptoms of suboptimal emotional and physical health. Significant increases were seen in serum BDNF, MPOD, and AOP. These findings illustrate the impact that reduction in systemic and local oxidative stress can have on many aspects of health and performance. Determining the basis (whether systemic or a more central), and neurophysiological pathway(s) for these effects is a question that warrants further study. Future research directions also include examining effects downstream from those described in the present studies, such as cognitive performance.