The present studies examined the pathogenesis of focal glomerular sclerosis in aging rats. A marked difference in development of the lesion was noted between males and females, and strain variability was an important factor. Increased glomerular basement membrane permeability with loss of selectivity unrelated to changes in glomerular sialoprotein occurred with aging and was accompanied by increasing proteinuria. Noncomplement-fixing mesangial deposits of rat IgM were present after 1 month of age and were also found in lesser amounts in germfree rats. Fluoresceinated eluates of rat kidneys did not have antibody activity against rat serum or tissue antigens. There was no evidence for a pathogenetic role of IgM deposits. Rat IgG, IgA, IgE, C3, and fibrin were occasionally found in sclerotic areas. Analysis of multiple histologic sections revealed a close correlation between aging and glomerular pathology, with a poor correlation between tubular damage and aging. Glomerular damage appeared to be the initial event leading to tubular damage. Indirect evidence suggests that a relative thymic deficiency may play an important role in the pathogenesis of the lesion.