Inosine administered into the renal artery improves renal ischemic tolerance. The study was designed to establish the limitations of this measure by comparing its effectiveness with that of regional hypothermia and to test the possibility of combining inosine and hypothermia in prolonged renal hypothermia. In uninephrectomized dogs, the remaining kidney was subjected to 2 h of ischemia under inosine protection; perfusion cooling, or no protection (experiment A), or to 90 min of warm ischemia plus inosine plus 90 min of cold ischemia; 90 min of warm plus 90 min of cold ischemia, or 180 min of cold ischemia (experiment B). Whereas perfusion cooling reliably prevented permanent loss of renal function even after 180 min of ischemia, inosine was clearly inadequate for protection against warm ischemia exceeding 90 min, but effective in shorter periods of ischemia with some unreliability in borderline cases. Inosine protection can be combined with hypothermia in a sequential manner if extended ischemia becomes necessary unexpectedly. For clinical use, however, it seems safer to commence with hypothermia after 60 min of inosine-protected warm ischemia. Simultaneous balloon occlusion of the renal artery and transcatheter perfusion cooling facilitates the clinical applicability of these results.