Spironolactone, an aldosterone antagonist, has been found effective in the treatment of certain forms of hypertension, ascites, and edematous conditions. Since patients may receive daily doses of spironolactone for many years, it is important to determine the chronic effects on tissues. This study reviews the tissue changes in rats, dogs, and monkeys receiving spironolactone daily for up to two years. Dose levels were frequently in excess of 100 times the recommended human dose. The pituitary, adrenals, and kidneys of all animals showed no significant changes. Histologic changes were noted in rat livers, thyroid, and male internal genitalia. There were alterations in monkey testes and male mammary glands. This study found no evidence to suggest that spironolactone is tumorigenic or carcinogenic. Species differences in metabolism may account for the diversity of tissue observations.