Relatively little is known about the physiological response and mortality consequences of the return of anadromous fish to freshwater (FW). We explored the consequences of the return to FW by collecting maturing sockeye salmon from the marine waters off the mouth of the Fraser River and holding approximately 50 sockeye in each of five treatments: saltwater (SW; salinity = 28 ppt), iso-osmotic water (ISO; 13 ppt), FW (0 ppt), SW + gonadotropin-releasing hormone (SW + GnRH), and FW + GnRH. Exogenous GnRH treatments were intended to accelerate maturation. Results demonstrate that gill Na(+),K(+) ATPase activity, sex steroid concentrations, and cortisol levels were highly responsive to experimental manipulations and followed predicted trajectories (i.e., FW + GnRH sockeye were the most mature and FW adapted). There were few among-treatment differences in hematocrit and plasma concentrations of lactate, glucose, Na(+), Cl(-), and plasma osmolality among sockeye that survived to the end of treatments, indicating that sockeye rigorously maintain internal homeostatic conditions while alive. There were large among-treatment differences in mortality (SW+GnRH > SW> FW+GnRH > FW=ISO), and each treatment experienced a notable increase in mortality rate around the fifth day of treatment. Our results indicate that salinity represented a modestly larger challenge to the experimental sockeye than did the artificially accelerated sexual maturation. Our results also suggest that maturing sockeye either successfully acclimate to FW within 5 d of exposure or perish. These findings are consistent with the predictions of the theory of anadromy, in suggesting that the return of adults to FW can be physiologically challenging and can represent a period of significant natural mortality.