The peripheral conversion of the prohormone 3,5,3',5'-tetraiodothyronine (T4) to the biologically active 3,5,3'-triiodothyronine (T3), via enzymatic deiodination by deiodinases, is an important pathway in thyroid hormone metabolism. The aim of this study was to test if thyroid hormones and cortisol, as well as the outer ring deiodination (ORD) metabolic pathway, are involved in the osmoregulatory response of Senegalese sole (Solea senegalensis, Kaup 1858). We measured osmoregulatory and endocrine parameters in immature juveniles S. senegalensis acclimated to seawater (SW, 38 per thousand) and that were transferred and allowed to acclimate to different salinities (5 per thousand, 15 per thousand, 38 per thousand and 55 per thousand) for 17 days. An adjustment and a chronic regulatory period were identified following acclimation. The adjustment period immediately follows the transfer, and is characterized by altered plasma osmolalities. During this period, plasma cortisol levels increased while plasma free T4 (fT4) levels decreased. Both hormones levels returned to normal values on day 3 post-transfer. In the adjustment period, renal and hepatic ORD activities had increased concomitantly with the decrease in plasma fT4 levels in fishes transferred to extreme salinities (5 per thousand and 55 per thousand). In the chronic regulatory period, where plasma osmolality returned to normal values, plasma cortisol had increased, whereas plasma fT4 levels decreased in animals that were transferred to salinities other than SW. No major changes were observed in branchial ORD activity throughout the experiment. The inverse relationship between plasma cortisol and fT4 suggests an interaction between these hormones during both osmoregulatory periods while ORD pathway can be important in the short-term adjustment period.