It has recently been proposed that renal cortical interstitial fibrosis is causally related to progressive decreases in glomerular filtration rate in a variety of renal diseases including glomerulonephritis. One hundred and eighty-eight renal biopsies in 81 patients with mesangial IgA nephropathy were analyzed for the percentage of relative interstitial volume by a point-counting technique. These data were correlated with serum creatinine, endogenous creatinine, endogenous creatinine clearance, and from age-matched donors were used as controls for the interstitial volume measurement. There was a negative nonlinear correlation between percentage of interstitial volume measurement. There was a negative nonlinear correlation between percentage of interstitial volume and creatinine clearance (r = 0.601, p less than 0.001). These correlations were not explained by age. However, serial biopsies in 39 patients clearly demonstrated that the percentage of interstitial volume could be dissociated from creatinine clearance. The prognosis in individual patients for progression to chronic renal failure could not be predicted from the relative interstitial volume at initial biopsy. Patients with mesangial IgA nephropathy demonstrated higher interstitial volumes than age-matched cadaver donors (p less than 0.001). Although interstitial volume and creatinine clearance are inversely related, the ability to dissociate these two variables in serial biopsies draws into question the hypothesis that interstitial fibrosis is causally related to changes in creatinine clearance. Studies to validate this hypothesis should involve patients followed with serial biopsies and renal function studies. In mesangial IgA nephropathy, interstitial changes are most likely secondary to the activity of the glomerular process.