SUMMARY. This study was performed on the hindpaws of anesthetized rabbits to determine the effects of acute saline expansion (10% body weight) on the extravascular distribution of water and plasma proteins. Prenodal lymph was collected separately from skin and muscle of the hindlegs. In samples of excised heel skin and gastrocnemius muscle, the extracellular and plasma spaces were measured with 51 Cr EDTA and 125 I albumin, respectively. The albumin and IgG spaces were calculated from measurements of the endogenous albumin and IgG concentrations in samples of plasma, lymph, and tissue extracts, by immunochemical techniques. Four hours after expansion, lymph flow from both tissues was more than 3 times greater than control, while the interstitial volume was increased by 20% in skin and 2.3 times for muscle. The elevated lymph flow was accompanied by a decrease in the lymph:plasma concentration ratio. The extravascular mass of albumin was 9.36 ± 0.61 and 3.93 ± 0.31 mg/g dry weight for control skin and skeletal muscle, respectively. The IgG mass was 2.62 ± 0.47 and 0.717 ± 0.084 mg/g dry weight for skin and muscle. Saline expansion resulted in a 41% increase in the extravascular albumin mass in muscle and no change in albumin mass in skin. The extravascular IgG mass increased by 58% in skin and 49% in muscle. The calculated excluded volume fraction for albumin decreased in both tissues and for IgG decreased in muscle. In skin, the IgG-excluded volume fraction could not be calculated after expansion since the apparent tissue concentration was greater than lymph, indicating interstitial concentration gradients for this molecule. Acute saline expansion resulted in a shift of plasma proteins from plasma to the extravascular space of skin and skeletal muscle. (Circ Res 51: [305][306][307][308][309][310][311][312][313] 1982)