The activities of brain renin and cathepsin D were measured in brain regions of 10 dogs on a normal sodium intake (65 mEq Na+/day) and 10 other dogs placed on a low sodium diet (less than 4 mEq Na+/day) for 21 days and given a diuretic. The purpose of this study was twofold: to assess the effect of sodium depletion on brain renin activity; and to assess in the same regions alterations in brain renin and cathepsin D activities. Sodium depletion caused a ninefold increase in plasma renin activity, hemoconcentration, and hyponatremia. In the presence of marked hyperreninemia, the average cerebral renin activity was reduced significantly; the most pronounced changes occurred in the upper and lower brain-stem regions. Cerebrospinal fluid renin was increased by 30%, but this change was not significant in sodium-depleted dogs. There were no significant alterations in cathepsin D activity whether assessed in total or regional brain areas. These observations support the view that there is an inverse relationship between plasma and brain renin activity in chronically sodium-depleted dogs. Additionally, evidence is provided that brain renin activity is modified independently from cathepsin D activity.