The sulfonamide derivative diuretics acetazolamide, metolazone and furosemide produce differing degrees of natriuresis and varying patterns of phosphate excretion. At least part of the explanation for these diverse actions could be related to divergent effects of the drugs on total renal blood flow (TRBF) and its intracortical distribution (IBFD). To test this hypothesis, and to determine if a consistent thesis regarding alterations in interenal blood flow could be developed, clearance studies were performed in chronically thyroparathyroidectomized dogs in which radioactive microsphere methodology was utilized to evaluate the distribution of blood flow within the renal cortex. These data were then compared with those available in the literature. The variations which the drugs induced in TRBF and IBFD did not help to explain the differences in their diuretic actions. However, a consistent hypothesis relating natriuresis, perfusion pressure, renal vascular resistance, TRBF and IBFD could be developed based on the data from this study and those available in the literature.