Previous studies from our laboratory have shown that human immunoglobulin light chains (LC) can be toxic to the epithelium of the rat proximal tubule. To examine the toxicity of monoclonal LC's in man, 11 kidney specimens (EXP group) obtained from patients with monotypical LC-related renal disease (7 lambda, 4 kappa), documented by the presence of monoclonal LC's in the serum or urine and in the tissue, were examined by light, immunofluorescence, electron, and immunoelectron microscopy. This EXP group had monotypical LC deposition in the tubules and/or the glomeruli and did not have evidence of intraluminal LC precipitation and cast formation, which alters tubule morphology. A control group (CON; N = 12) of kidney specimens was obtained from patients who had proteinuria greater than 2.5 g/24 hr and mean age (49 ± 4 vs. 59 ± 3 years; P = NS), serum creatinine concentration (2.4 ± 0.5 vs. 3.2 ± 1.5 mg/dl; P = NS) and creatinine clearance (65 ± 13 vs. 63 ± 12 ml/min; P = NS) similar to the EXP group. All of the EXP specimens demonstrated varying degrees of proximal tubule damage, manifested by cell vacuolation, desquamation, loss of the luminal brush border, and, often, coagulation necrosis. The proximal tubules of this EXP group also had an increase in endocytic activity and marked activation of the lysosomal system; some of the lysosomes appeared distorted and atypical. Intralysosomal structures suggestive of crystals were also occasionally seen. In contrast, the only morphologic alterations in the CON specimens were increased endocytic activity and an activated lysosomal system in two of the specimens and mild focal vacuolation in three specimens; atypical lysosomes were not seen. Thus, those patients with monoclonal LC accumulation in the proximal tubules developed damage and necrosis. The presence of atypical lysosomes in the proximal tubules may serve as a morphologic marker of monoclonal LC-related renal disease.