Protein concentration and hydrostatic pressure were measured in subcutaneous tissue of rats during development of aminonucleoside nephrosis. Samples of interstitial fluid for protein analysis were collected from subcutaneous tissue by a wick method, and hydrostatic pressure was measured by a modified Scholander technique. When the serum protein concentration was reduced from 6.1 to 4.8 g/100 ml, interstitial fluid protein concentration fell from 3.0 to 1.1 g/100 ml. This corresponds to a reduction of calculated oncotic pressures from 18.0 to 13.0 mm Hg and from 7.8 to 3.0 mm Hg in serum and interstitial fluid, respectively, thus leaving a nearly constant net transcapillary oncotic pressure. When serum protein concentration was further reduced to 3.8 g/100 ml, interstitial fluid protein concentration was reduced to 0.5 g/100 ml, reducing net transcapillary oncotic pressure by 2-3 mm Hg. The average hydrostatic pressure in subcutis was 1.0 mm Hg subatmospheric under control conditions and did not change during hypoproteinemia. The results indicate that a reduction of interstitial protein concentration is an important factor in preventing edema formation in hypoproteinemia.