Coastal hypoxia affects the survival, behavior, and reproduction of individual local marine organisms, and the abundance, biomass, and biodiversity of coastal ecosystems. In this study, we investigated the chronic effects of hypoxia on the metabolomics in the gills of Ruditapes (R.) philippinarum. The results indicated significant alterations in the metabolite profiles in the gills of the hypoxia-treated clams, in comparison with those maintained under normoxia. The levels of betaine, taurine, glycine, isoleucine, and alanine were significantly reduced, suggesting a disturbance of osmotic balance associated with hypoxia. Meanwhile, metabolites involved in energy metabolism, such as alanine and succinate, were also affected. Dramatic histopathological changes were observed in the gills and hepatopancreases of R. philippinarum grown in hypoxic waters, demonstrating tissue damages apparently caused by long-term exposure to hypoxia. Our findings suggest that hypoxia significantly affects the physiology of R. philippinarum, even at a sub-lethal level, and impedes health of the clams. (C) 2016 Elsevier Ltd. All rights reserved.