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This study was designed to measure the effective concentration of plasma albumin in the interstitial space of human dermis. Discs of tissue taken postmortem from four donors have been separately analyzed for their content of plasma albumin and equilibrated with 125I-labeled monomeric plasma albumin in a specially designed cell which limited tissue swelling. The equilibrated discs and their surrounding fluid were assayed for radioactivity and the tissue space accessible to albumin was calculated after correction for swelling. The albumin content of serum was also measured. The concentration of albumin in the accessible space of the tissue ranged from 0.45 to 0.93 that in serum, averaging 0.68. The fraction of the total interstitial fluid accessible to albumin averaged, for three normal dermises, 0.35 and for an overhydrated specimen, 0.51. Thus, the effect of volume exclusion should be considered in measurements of the concentrations of plasma proteins in tissue.