The Amazonian oscar is extremely resistant to hypoxia, and tolerance scales with size. Overall, ionoregulatory responses of small (∼15 g) and large oscars (∼200 g) to hypoxia were qualitatively similar, but the latter were more effective. Large oscars exhibited a rapid reduction in unidirectional Na+ uptake rate at the gills during acute hypoxia (Po2 ∼10 mmHg), which intensified with time (7 or 8 h); Na+ efflux rates were also reduced, so net balance was little affected. The inhibitions were virtually immediate (1st h) and preceded a later 60% reduction (at 3 h) in gill Na+-K+-ATPase activity, reflected in a 60% reduction in maximum Na+ uptake capacity without change in affinity (Km) for Na+. Upon acute restoration of normoxia, recovery of Na+ uptake was delayed for 1 h. These data suggest that dual mechanisms may be involved (e.g., immediate effects of O2 availability on transporters, channels, or permeability, slower effects of Na+-K+-ATPase regulation). Ammonia excretion appeared to be linked indirectly to Na+ uptake, exhibiting a Michaelis-Menten relationship with external [Na+], but the Km was less than for Na+ uptake. During hypoxia, ammonia excretion fell in a similar manner to Na+ fluxes, with a delayed recovery upon normoxia restoration, but the relationship with [Na+] was blocked. Reductions in ammonia excretion were greater than in urea excretion. Plasma ammonia rose moderately over 3 h hypoxia, suggesting that inhibition of excretion was greater than inhibition of ammonia production. Overall, the oscar maintains excellent homeostasis of ionoregulation and N-balance during severe hypoxia.