Marine organisms are constantly exposed to multiple stressors creating a range of associated environmental and ecotoxicological risks. Several stressors have been identified as key drivers of environmental change that may significantly influence marine near-shore systems. These include increased frequency and duration of extreme rainy events and drought periods, arising from climate change, and the constant discharge of contaminants into aquatic systems. A growing body of evidence demonstrates that climate change can have direct and indirect impacts on marine organisms although the combined effects with other stressors, namely with metals and metalloids, have received very little attention to date.The present study evaluated the biochemical alterations induced in the clam Ruditapes philippinarum, also known as Manila clam, when simultaneously exposed (96h) to different arsenic concentrations (0, 4 and 17mg/L) and a range of salinities (14, 21, 28, 35 and 42g/L). Results obtained revealed that, when acting alone, both stressors induced oxidative stress in clams, with higher LPO levels and lower GSTs activity induced by As contamination, and a stronger inhibition of the antioxidant defenses induced by salinity increase. Furthermore, when exposed to the combination of both stressors, clams experienced stronger biochemical alterations, presenting higher LPO increases and greater decreases of antioxidant enzymes, especially noticed at higher salinities.The present findings may indicate that climate change, including predicted drought periods that will increase salinities in aquatic systems, will seriously affect the clam R. philippinarum, especially those inhabiting contaminated ecosystems.