To investigate the relationship beween atherosclerotic vascular disease and age-associated changes in the normal human kidney, autopsy findings and renal histology from 57 individuals with mild systemic atherosclerosis (group I), were compared to 57 sex- and age-matched individuals with moderate-to-severe atherosclerosis (group II). Age, sex, body build, the presence or absence of hypertension, semiquantitative aorta and coronary-artery atherosclerosis scores, organ weights, and the percent of globally sclerotic glomeruli were determined in each. Glomerular area, arcuate/interlobular arteries, and percent interstitial fibrosis were measured using standard morphometric techniques. Group I individuals had a 8.3 ± 7.0% incidence of sclerotic glomeruli, compared to 15.4 ± 16.3% in group II (mean ± SD, P < 0.01). Relative intrarenal arterial wall area was increased in group II (60 ± 12%) compared to group I (55 ± 11%, P < 0.05). The mean glomerular area of nonsclerotic glomeruli was greater in group II (23,700 ± 6,000 sq μ) than in group I (19,600 ± 3,700 sq μ, P < 0.01), suggesting that there were compensatory increases in glomerular size in group II. Interstitial fibrosis was similar in both groups. The relative impact of age, sex, body build, hypertension, systemic atherosclerosis, intrarenal vascular disease and interstitial fibrosis on glomerulosclerosis and glomerular size was investigated using multiple linear regression. Both age and intrarenal vascular disease exhibited highly significant, independent associations with glomerulosclerosis. Glomerular area was positively correlated with heart weight and coronary artery atherosclerosis. In contrast, there was no independent correlation between glomerular area and glomerulosclerosis. These results indicated that a significant portion of the glomerulosclerosis that occurs in aging humans is linked to atherosclerosis. Age-associated compensatory increases in glomerular size, on the other hand, are related to heart disease, and not to glomerulosclerosis per se.