In the last few decades, marine hypoxia has become one of the major ecological concerns in the world, because of the increase of excessive anthropogenic input of nutrients and organic matter into coastal seawater [1]. Benthic communities are the most sensitive parts of the coastal ecosystem to eutrophication and resulting hypoxia [2]. High production in stratified waters results from nutrient enrichment and can cause hypoxic or anoxic bottom waters because of the subsequent deposition of algal biomass [3]. Marine organisms are directly affected by hypoxia at various levels of organization and behavioural, biochemical and physiological responses to limited availability of oxygen have been well studied in fish and marine invertebrates [4]. Most of the invertebrate species that inhabit the intertidal zone, and especially sedentary ones, have developed mechanisms for surviving twicedaily oxygen deprivation at low tide. Depression of metabolic rate can be considered as one of the most important adaptations for hypoxia endurance [5,6]. Many marine molluscs do indeed show reversible protein phosphorylation to limit the activity of many enzymes and functional proteins during anoxia [5,7]. The same response to hypoxia has already been The molecular response to hypoxia stress in aquatic invertebrates remains relatively unknown. In this study, we investigated the response of the Pacific oyster Crassostrea gigas to hypoxia under experimental conditions and focused on the analysis of the differential expression patterns of specific genes associated with hypoxia response. A suppression subtractive hybridization method was used to identify specific hypoxia up-and downregulated genes, in gills, mantle and digestive gland, after 7-10 days and 24 days of exposure. This method revealed 616 different sequences corresponding to 12 major physiological functions. The expression of eight potentially regulated genes was analysed by RT-PCR in different tissues at different sampling times over the time course of hypoxia. These genes are implicated in different physiological pathways such as respiration (carbonic anhydrase), carbohydrate metabolism (glycogen phosphorylase), lipid metabolism (delta-9 desaturase), oxidative metabolism and the immune system (glutathione peroxidase), protein regulation (BTF3, transcription factor), nucleic acid regulation (myc homologue), metal sequestration (putative metallothionein) and stress response (heat shock protein 70). Stress proteins (metallothioneins and heat shock proteins) were also quantified. This study contributes to the characterization of many potential genetic markers that could be used in future environmental monitoring, and could lead to explore new mechanisms of stress tolerance in marine mollusc species.Abbreviations GPx, glutathione peroxidase; HIF-1, hypoxia-inducible factor-1; HSP, heat shock protein; MT, metallothionein; SSH, suppression subtractive hybridization.