The immunomorphological expressions of monoclonal light-chain-related renal diseases (MLCRRD) are extremely varied but have a common pathogenetic feature: monoclonal light-chain deposition. The underlying cellular events involved in these processes are likely a reflection of interactions of a complex cascade of inciting and modulating factors. This study explored the potential role of growth factors in MLCRRD by examining the expression of insulin-like growth factor (IGF-I), fibroblast growth factor (FGF), transforming growth factor-beta (TGF-beta), and platelet-derived growth factor A chain (PDGF-A) and B chain (PDGF-B) in 36 cases of MLCRRD. All growth factors examined were expressed in tubules, primarily proximal, but to varying extent. Intensity of IGF-I and TGF-beta tubular staining correlated with tubular injury and interstitial fibrosis. Intensity of tubular staining with antibodies to FGF also correlated with interstitial fibrosis. Platelet-derived growth factor B chain was strongly detected in glomeruli and, in some cases, in vascular structures. Transforming growth factor-beta was detected only in glomeruli of three patients with nodular glomerulopathy associated with light-chain-deposition disease. Insulin-like growth factor, FGF, and PDGF-A were not detected in glomeruli or vessels in any of the cases. Proliferating cell nuclear antigen (PCNA) staining in tubules and glomeruli was markedly increased in light-chain-deposition disease and less but still significantly increased above control values in the other variants of MLCRRD. These results suggested: (1) a correlation between IGF-I and TGF-beta staining in the tubular interstitium and tubular damage; (2) a correlation between IGF-I, TGF-beta, and FGF staining in the tubular interstitium and interstitial fibrosis; (3) a likely important role for PDGF-B activation in certain glomerular alterations that occur in MLCRRD; (4) a role for TGF-beta in light-chain-deposition disease; and (5) the presence of a significant proliferation signal in all cases of MLCRRD but most notably in light-chain-deposition disease in glomerular and tubular compartments. A cascade of events related to growth factor activation appears to play a fundamental role in the pathophysiological processes governing MLCRRD.