The purpose of this study is to explore the historical background of edema as a prognostic sign in popes, a special category of medical subjects whose health status was closely monitored and chronicled because of their unique important status in the events of their times. Nine out of 51 popes, who reigned in the years 1555–1978, died edematous at a mean age of 75.5 years of age. The cause of edema was: heart failure for John Paul I, liver disease, obstructive nephropathy associated with anemia for Paul IV, who also suffered from deep vein thrombosis, and malnutrition for Innocent XIII. Chronic kidney disease due to renal stones of gouty origin caused edema in Clement VIII, Clement X, Clement XI, and Benedict XIV. Obstructive nephropathy due to renal stones of non-gouty origin caused edema in Clement XIII, whereas toxic nephropathy due to the use of mercurials caused edema in Clement XIV. Innocent XI, Benedict XIV, and Clement XIV were bled before death because of impending pulmonary edema. It is not surprising that chronic kidney disease was a significant cause of edema in popes with chronic kidney disease which is associated with impaired sodium excretion. The edema was likely aggravated by the excessive dietary salt intake of the period when the importance of sodium chloride restriction was still not discovered and effective diuretic agents were not available.