This study investigates the effects of hypophysectomy and subsequent hormone replacement therapy upon the hormonal and osmoregulatory status of coho salmon, Oncorhynchus kisutch, in 7% seawater (SW) and SW. Following hypophysectomy, coho salmon were injected every 2 days for 8 days with thyroxine, growth hormone, and cortisol, alone or in combinations, and sampled 2 days after the final injection. Increased environmental salinity raises plasma sodium, calcium, and magnesium levels, as well as plasma osmolality. Cortisol is hypercalcemic and thyroxine is hypocalcemic in hypophysectomized salmon, but it is unclear whether these effects are due directly to calcium regulation or are the consequence of general effects on the plasma osmotic/ionic balance. Growth hormone and thyroxine together, but not separately, decrease and increase magnesium levels, at low and high environmental salinities, respectively, indicating a complex endocrine control of plasma magnesium. Gill Na+, K+-ATPase activity in hypophysectomized salmon is stimulated by growth hormone and cortisol, but inhibited by thyroxine and raised environmental salinity. This implies a complex endocrine control and indicates that hormonal support is needed to sustain or raise gill Na+, K+-ATPase activity in seawater. Increased environmental salinity induces elevation of plasma cortisol levels in apparent absence of pituitary control, indicating that the interrenals may respond to changes in external and/or internal environment, either directly or indirectly through extrapituitary hormonal or nervous control. Cortisol is a potent inhibitor of calcitonin secretion, as seen by the large decrease in plasma calcitonin levels in cortisol-treated hypophysectomized fish. The study was carried out at a time when thyroxine plasma levels were low. These basal levels were not affected by hypophysectomy, possibly indicating a basal release of thyroxine from the thyroid without stimulatory support of the pituitary gland.