Ruditapes philippinarum , a clam that thrives in intertidal zones of various salinities, is a useful biomonitor to marine contaminants. We investigated the infl uence of dilution to 75% and 50% of normal seawater salinity (31.1) on the responses of the digestive gland of R . philippinarum to arsenic exposure (20 μg/L), using nuclear magnetic resonance (NMR)-based metabolomics. After acute arsenic exposure for 48 h, salinity-dependent differential metabolic responses were detected. In normal seawater, arsenic exposure increased the concentrations of branched-chain amino acids, and of threonine, proline, phosphocholine and adenosine, and it decreased the levels of alanine, hypotaurine, glucose, glycogen and ATP in the digestive glands. Differential changes in metabolic biomarkers observed at lower salinity (~23.3) included elevation of succinate, taurine and ATP, and depletion of branched-chain amino acids, threonine and glutamine. Unique effects of arsenic at the lowest salinity (~15.6) included down-regulation of glutamate, succinate and ADP, and up-regulation of phosphocholine. We conclude that salinity infl uences the metabolic responses of this clam to arsenic.