In the Mekong Delta, striped catfish are faced with chronic salinity stress related to saltwater intrusion induced by global climatic changes. In this study, striped catfish juveniles were submitted to a prolonged salinity stress (up to 10 ppt) over three weeks followed by infection with a virulent bacterial strain, Edwardsiella ictaluri. Osmoregulatory parameters were investigated. In addition, a label free quantitative proteomics workflow was performed on kidneys. The workflow consisted of an initial global profiling of relative peptide abundances (by LC/MS, peak area quantification based on extracted ion currents), followed by identification (by MS/MS). The aim of the study was to highlight specific functional pathways modified during realistic salinity stress, particularly those involved in immunity. In kidney proteome, 2483 proteins were identified, of which 400 proteins were differentially expressed between the freshwater and the saline water conditions. Several pathways and functional categories were highlighted, mostly related to energy metabolism, protein metabolism, actin cytoskeleton, signaling, immunity, and detoxification. In particular, the responsiveness of proteins involved in small GTPases and Mitogen Activated Protein Kinase p38 signaling, phagolysosome maturation, and T-cells regulation is discussed. Statement of significance In the Mekong River Delta (Vietnam), striped catfish production is threatened by extensive sea water intrusion exacerbated by sea level rise. In fish, the effect of chronic exposure to salinity stress on immune capacities and response to disease has been poorly investigated. This study aims to highlight the main molecular changes occurring in the kidney during acclimation to salinity stress, particularly those involved in the immune defences of fish.