Rainbow trout (Oncorhynchus mykiss) were exposed to sublethal concentrations of copper (Cu, 14 μg/liter) and zinc (Zn, 57 and 81 μg/liter) for a 21-day period. The four treatments included a control, a Cu control, a Cu and low-Zn treatment and a Cu and high-Zn treatment. Selected parameters [e.g., hemoglobin (Hb), hematocrit (Hct), plasma glucose, lactate and cortisol, differential leukocyte count, respiratory burst, tissue metal concentrations, hepatic metallothionein (MT), brain acetylcholinesterase (AChE)] were evaluated at 2, 7, 14, and 21 days of exposure. Whole blood and plasma parameters were not altered by exposure to metals. The percentage of lymphocytes was consistently decreased in the three metal treatments, while percentages of neutrophils and monocytes were increased. Respiratory burst activity was elevated in all metal treatments. Gill Zn concentration was highly variable, with no significant alterations occurring. Gill Cu concentration was elevated above control levels in all metal treatments. Gill Cu concentration in the two Cu/Zn treatments was also elevated above levels in the Cu control. Hepatic metal concentrations and MT levels were not altered from control values. Measurements of brain AChE indicated an elevation in this parameter across metal treatments. In general, alterations in physiological parameters appeared to be due to Cu, with Zn having no interactive effect.