The effect of long-term freshwater acclimation on the blood and plasma ion composition of Red Drum Sciaenops ocellatus was investigated with the goal of elucidating the necessity of ion remediation. Four replicates (n = 50) of freshwater-acclimated (FW) fish (1.6 ± 0.2 g) were raised in 25-m(3) tanks supported by 140,000 L of recirculating water. Four replicates (n = 50) of seawater (SW) fish groups were placed in 40-m(3) offshore cages at 32-35 psu. Blood was collected from 100 fish (FW = 578 ± 50 g; SW = 686 ± 45 g) of each group (FW, SW) after 8 months of rearing. During the grow-out phase, the survival of FW and SW fish was 57.5% and 92.2%, respectively. The water ion composition (mainly the Ca(2+)/K(+) [43%] and Ca(2+)/Mg(2+) ratios [1%]) explained 56.6% of the plasmatic ion variability in the fish groups. Freshwater exposure produced significant reductions in osmolality and in several plasma indicators (Na(+), Cl(-), and Mg(2+)); the K(+) levels from FW fish were the most compromised parameter. The water Ca(2+)/Na(+) ratio had a greater influence (44%) on the plasma chemistry parameters, mainly glucose and creatinine. Freshwater-acclimated fish had a higher percentage of hematocrit, hemoglobin, and red blood cells than SW fish, but the water quality explained only 12.5% of the blood parameter variability between the FW and SW groups. The results support the conclusion that Red Drum tolerates salinity variations and can adopt a relatively stable condition for short periods; however, the data suggest that Red Drum have only a limited ability to withstand a hyposmotic environment for long periods due to their limited ability in maintaining K(+) concentrations without external supplementation. Freshwater environments with high Ca(2+)/Na(+), Ca(2+)/K(+), and Ca(2+)/Mg(2+) ratios appear to be a chronic stress factor that should be considered in future experiments.