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Salinity in the oceans is changing due to climate change and global warming. Intense rainfalls and freshwater runoff decrease salinity along the coastal areas. In contrast, intense drought seasons and river damming have certainly increased salinity in lagoons and estuaries. Few studies have focused on aspects of the biology and culture of oyster Crassostrea corteziensis, but until now, physiological and immunological responses in this species have not been assessed under acute hypo- and hypersaline stress conditions. Oysters obtained from a local farm were acclimated for three weeks in laboratory conditions. To avoid closure of oyster valves during salinity induced-stress conditions, a notch was done on each organism shell not only to facilitate oyster tissue exposure to rearing water but also for sampling hemolymph. Oysters (N = 180) were abruptly exposed to three salinity treatments: (HO) hypo-, (C) control, and (HP) hypersaline stress conditions (10, 35, and 50 PSU, respectively). Four oysters per treatment were sampled at 1, 2, 3, 6, 12, 24, and 48 h after exposure. Hemolymph osmolality, water content and total protein concentration in tissues, metabolic and immune responses were assessed for each organism. Oyster survival was not different among treatments and was maintained above 96% at the end of the experimental trial. Hemolymph osmolality reached the value of rearing water at 6 and 48 h of exposure to HP and HO stress conditions, where oysters exposed to salinity increase showed less resilience than those to decrease. Higher glucose levels in plasma and lower ones of hemocyanin were assessed in the oysters exposed to HP compared to HO conditions, suggesting more stressful conditions or susceptibility of oysters during salinity increase. Total hemocyte (THC), hyalinocyte (HC), and granulocyte (GC) counts decreased in oysters exposed to HP condition, while total and differential hemocyte counts were similar among oysters exposed to HO and control conditions. Despite hemocyte phagocytosis was not different among treatments, viability decreased in those exposed to HP condition. Contrastingly, superoxide anion (SOA) production (oxidative capacity) increased in oysters exposed to both induced salinity-stress conditions, which suggest susceptibility increase in oysters, particularly during salinity increase. The results show that HP condition is particularly stressful for C. corteziensis. In turn, this condition could increase both their vulnerability to other environmental stressors, such as temperature and/or acidification or susceptibility to opportunistic pathogenic microorganisms that cause the most common oyster diseases., (Copyright © 2021 Elsevier Ltd. All rights reserved.)