Excessive and prolonged generation of superoxide (O2-) and nitric oxide (NO) from inflammatory leukocytes is associated with several lifestyle-related diseases, including cancer. In the present study, we screened 19 natural carotenoids for their modifying effects on O2- and NO generation from differentiated human promyelocytic HL-60 cells and mouse macrophage RAW 264.7 cells, respectively. Of the carotenoids tested, halocynthiaxanthin, isolated from oysters, showed the highest suppressive effect on the generation of both free radicals. The inhibitory potencies of certain carotenoids on radical generation markedly exceeded that of beta-carotene. In addition, some important structural moieties regulating radical generation suppression are discussed.