The rank order of diuretic efficacy of furosemide analogs, e.g. bumetanide and piretanide, in humans is reflected better by their ability to inhibit Na+, K+-cotransport in human red blood cells than by their natriuretic activity in rats. High ceiling diuretics which are structurally unrelated to sulfamoyl diuretics, e.g. muzolimine, tizolemide, MK 447, may be similarly effective in rat and man, but by acting via other mechanisms cannot be detected by use of the Na+, K+-cotransport system. On the other hand, a possible conversion of such compounds to metabolites active in the cotransport system cannot be ruled out. In contrast to ethacrynic acid, the weak inhibitory activity of muzolimine on the Na+, K+-cotransport was not potentiated by cysteine. These results suggest that the diuretic activity of muzolimine is not caused by inhibition of Na+, K+-cotransport.