Gene polymorphisms provide a means to obtain unconfounded associations between carotenoids and various health outcomes. In the present study, we tested whether gene polymorphisms and gene scores linked to low serum carotenoid status are related to metabolic disturbance and depressive symptoms in African-American adults residing in Baltimore city, MD, using cross-sectional data from the Healthy Aging in Neighborhoods of Diversity across the Life Span study (age range 30–64 years, n 873–994). We examined twenty-four SNP of various gene loci that were previously shown to be associated with low serum carotenoid status (SNPlcar). Gene risk scores were created: five low specific-carotenoid risk scores (LSCRS: α-carotene, β-carotene, lutein+zeaxanthin, β-cryptoxanthin and lycopene) and one low total-carotenoid risk score (LTCRS: total carotenoids). SNPlcar, LSCRS and LTCRS were entered as predictors for a number of health outcomes. These included obesity, National Cholesterol Education Program Adult Treatment Panel III metabolic syndrome and its components, elevated homeostatic model assessment of insulin resistance, C-reactive protein, hyperuricaemia and elevated depressive symptoms (EDS, Center for Epidemiologic Studies-Depression score ≥ 16). Among the key findings, SNPlcar were not associated with the main outcomes after correction for multiple testing. However, an inverse association was found between the LTCRS and HDL-cholesterol (HDL-C) dyslipidaemia. Specifically, the α-carotene and β-cryptoxanthin LSCRS were associated with a lower odds of HDL-C dyslipidaemia. However, the β-cryptoxanthin LSCRS was linked to a higher odds of EDS, with a linear dose–response relationship. In summary, gene risk scores linked to low serum carotenoids had mixed effects on HDL-C dyslipidaemia and EDS. Further studies using larger African-American population samples are needed.