This study investigated the responses of Na+/K+-ATPase, Mg2+-ATPase and Ca2+-ATPase in the gill and muscle of a freshwater fish Oreochromis niloticus exposed to 1 mu g/mL of Cd and Zn and their mixture for different periods (0, 7, 14, 21 and 28 days). At the end of experimental periods, the activities Na+/K+-ATPase, Mg2+-ATPase and Ca2+-ATPase in gill tissues and only Ca2+-ATPase activity in muscle tissues were measured. Gill Na+/K+-ATPase activity generally decreased following single metal exposures, whereas their combinations increased its activity. Gill Ca2+-ATPase activity decreased relative to the control at most exposure times for single exposures of Zn and Cd, as well as for the combined exposure. There was no gill Ca2+-ATPase activity after 28 days of exposure to Zn and Cd combined. Mg2+-ATPase activity was not affected significantly in gill tissue by exposure to Zn and Cd individually or in combination. Muscle Ca2+-ATPase activity also decreased significantly following metal exposure, but not as greatly as in the gill tissue. Tissue protein levels were mostly unaffected by metal exposures. This study showed that certain ATPases are highly sensitive to metal exposure whether the metals are essential or non essential, and suggests using gill tissue Na+/K+-ATPase and Ca2+-ATPase as sensitive biomarkers in metal contaminated waters.