Cross-circulation through normal recipient dogs of blood from saline-loaded donor dogs that had escaped from desoxycorticosterone acetate (DCA) resulted in a sixfold rise in renal sodium excretion in the recipients. The change occurred without a detectable alteration in filtered sodium (FNa). To investigate the locus of secretion of a humoral factor responsible for the natriuresis, a series of ablational procedures was performed in DCA-escaped, saline-loaded donors. Nephrectomy, hepatectomy, or decapitation before saline loading and cross-circulation failed to block the increase in renal sodium excretion in the recipients. Analysis of periods during cross-circulation with a decrease in FNalower than the lowest control value showed that sodium excretion was elevated significantly above control levels in experiments with normal, hepatectomized, and decapitated donors. In contrast, with nephrectomized donors the increase in sodium excretion in the recipients was negligible. This finding points to the need for further study of the kidney as a possible source of a humoral factor in the control of renal salt excretion.