During protein depletion produced by plasmapheresis and a very low protein diet there is a proportionately greater decrease in extravascular, extracellular fluid protein than in plasma protein. A shift in the normal ratio of protein in these 2 compartments, approximately 1 to 1 in the dog, to over 2 to 1 as a result of depletion indicates an important, labile source of reserve protein for the plasma in the interstitial fluids. This reserve source is limited since a maximum drop of 50 per cent in the total exchangeable pool and of 75 per cent in the extravascular, extracellular protein occurred after both shorter and longer periods of depletion. Under the rigid conditions of these experiments additional plasma protein removal was associated with loss of weight despite adequate caloric intake. Investigation of the status of the interstitial fluid proteins in other conditions associated with disturbed protein metabolism seems warranted.