An accumulation of the connective tissue component, hyaluronan (HA), is known to occur in both syngeneic and allogeneic kidney grafts during the early postoperative period. The presence of HA in the interstitial tissue of the grafts is paralleled by an increased water content, suggesting a role for HA in the development of the transplantation edema. In the present work, the kidney content and distribution of HA was studied in a model of warm renal ischemia in the rat to investigate whether renal ischemia is associated with HA accumulation. Seventy-two hours after a period of warm renal ischemia (30 or 60 min) significantly higher amounts of HA were observed in the left kidney that had been exposed to ischemia, than in the right, healthy kidney. The most pronounced increase was found to occur in the cortex (20 to 40 times), a structure where there normally is almost no presence of HA. In addition, there was a correlation between the relative water content of the kidney and the amount of HA possible to extract from the tissue. The renal accumulation of HA and water was prevented by daily intravenous administration of hyaluronidase. We conclude that renal ischemia induces an accumulation of HA that may increase the risk for the development of interstitial edema, a situation that may be circumvented by hyaluronidase treatment.