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The effects of a cationic detergent, cetyl pyridinium chloride (CPC), on toad bladder epithelium were studied by means of electrophysiologic and sodium-flux measurements, chemical analysis, time-lapse phase-contrast cinemicrography and electron microscopy. At 10(-5) M, CPC caused a rapid loss of net sodium transport as reflected by the short-circuit current (SCC) but except for striking prominence of the glycocalyx, this dose caused no ultrastructural changes for at least 18 hours. Only a moderate decrease in resistance and increase in passive sodium flux were noted. At 10(-4) M, CPC caused a transient 1 to 2-minute increase in the bladder's rate of oxygen consumption followed by a decrease, and a rapid decline in SCC, followed a few minute later by a decrease in resistance accompanied by a greatly increased passive leak to sodium. A sequence of ultrastructural changes typical of other forms of lethal cell injury progressed to extensive cellular disruption by 1 hour after treatment with 10(-4) M CPC. In addition, unusual surface membrane changes were observed, consisting of extensive formation of vesicles and myelin figures at the cell surface. A significant fraction of the bladder's cholesterol content appeared in the incubation medium after 10(-4) M CPC treatment. With 10(-3) M CPC, a similar pattern of cellular degeneration proceeded much more rapidly, and in addition, the cellular remains reorganized into complex lamellar arrays resembling phospholipid crystalloids. The results are interpreted as indicating that in addition to inhibiting net sodium transport, CPC lethally injures cells by interfering with the function of the surface membrane as a permeability barrier, and in addition, leads to a drastic structural reorganization of membrane constituents.