During potassium depletion in rats, the skeletal muscles lose potassium and gain sodium, whereas the Na-K contents of the liver1, brain, cerebrospinal fluid2,3, erythrocytes and heart4 remain virtually constant for several weeks. Since the selective loss of potassium ions from the muscles may result from inhibition of the active Na-K transport 5, it is of interest to determine whether potassium depletion is associated with a reduced capacity for Na-K pumping. This study explores this possibility with measurements of 3H-ouabain binding and 42K uptake in soleus and extensor digitorum longus muscles obtained from rats or mice during potassium deficiency induced either by K-free diet, a diuretic or a potassium-binding resin. Potassium depletion leads to a pronounced (up to 78%) and reversible decrease in the total number of 3H- ouabain binding sites and a reduced capacity for Na-K pump-mediated 42K uptake. This decrease in the number of functional Na-K pumps may be of importance for the selective loss of potassium from skeletal muscle and its maintenance during potassium depletion. Furthermore, it favours the redistribution of digitalis glycosides from the periphery to the heart and provides an explanation for the increased digitalis toxicity seen in patients suffering from chronic potassium depletion.