The uptake and disposal of injected aggregated human albumin (AHA) by the glomerular mesangium of normal mice was evaluated by immunoelectron microscopy. The injected AHA rapidly entered the mesangial matrix channels via endothelial fenestra at the axial pole of the lobules and reached maximal concentrations at 8 hours after injection. Small quantities of AHA were endocytosed by mesangial cells. Significant filtration of the polydispersed AHA, which included molecular albumin, was observed across both the peripheral glomerular basement membrane and the mesangial glomerular basement membrane. The injected AHA was observed in the juxtaglomerular region, between lacis cells, and in the wall of arterioles at early time periods after injection. A heavy fraction of AHA (molecular weight, greater than 1 million) was also readily taken up by the region and was found in the interstitial space in the vicinity of glomeruli at 2 1/2 hours after injection. This study demonstrates a method for sequential study of the distribution in the kidney of protein macromolecules of great biologic significance. The study confirms the existence of an efferent limb of mesangial drainage to the region of the juxtaglomerular region and the renal interstitium. The fact that very large aggregates readily transited this pathway and were found in the interstitial space offers additional support for the hypothesis that the renal lymphatics may participate in the clearance of macromolecules from the glomerular mesangium.