A morphometric study was performed in dog atria to assess the effects of both single and repeated doses of doxorubicin on specific granules containing the natriuretic factor. Male beagle dogs were divided into 4 groups and treated i.v. as follows: groups A and B were controls and received isotonic saline; group C was given doxorubicin 2.4 mg/kg in a single injection; group D received doxorubicin 1.2 mg/kg once a week for 3 consecutive weeks. Samples of left atrium were taken 8 hours (groups A and C) or 28 days (groups B and D) after the last dose, and examined by the electron microscope. Compared with controls, the atrial tissue of group C dogs showed a significant increase in the number of specific granules; by contrast, the granularity was found to decrease significantly in the atria from group D dogs. These observations indicate a significant biphasic effect of doxorubicin on specific atrial granules of dog heart. The increase in granule density might be due to a block of the secretory process which is dependent on the metabolic energy supply. The reduction in cardiomyocyte granularity may be ascribed to the impairment of nucleic acid and protein synthesis induced by doxorubicin. Such alterations may play a significant role in doxorubicin-induced cardiovascular toxicity.