Hyperosmotic stress has often been investigated from osmoregulation perspectives while the effects of such stress on the immune capacity remain largely unexplored. In this study, striped catfish were submitted to three salinity profiles (freshwater, low saline water, saline water) during 20 days, followed by infection with a virulent bacteria, Edwardsiella ictaluri, responsible for the enteric septicaemia of catfish. Osmoregulatory (plasma osmolality, gill Na(+)K(+)ATPase), immune (blood cells, lysozyme activity, complement activity, respiratory burst) parameters and mortality rate were investigated. In addition, abundances of heat shock protein 70 and high mobility group box 1 were explored. With elevated salinity, plasma osmolality severely increased while gill Na(+)K(+)ATPase slightly increased. Salinity alone stimulated the number of granulocytes, lysozyme activity and respiratory burst but depleted the number of thrombocytes. Salinity in combination with infection stimulated the number of monocytes and ACH50. On the contrary, erythrocytes, hematocrit, heat shock protein 70 and high mobility group box 1 did not significantly vary with salinity profiles. Then, salinity induced earlier onset on mortalities after E. ictaluri inoculation whereas cumulative mortality reach 79.2%, 67.0% and 91.7% respectively in freshwater, low saline water and saline water. In conclusion, salinity stimulates several immune functions in striped catfish but prolonged exposure to excessive hyperosmotic condition may lead to excessive inflammatory response and death.