To clarify the production mechanism of atrial natriuretic peptide (ANP) in right (RA) and left atria (LA) in mitral valve disease, histopathological and immunohistocytochemical analyses were performed and ANP levels were investigated by radioimmunoassay (RIA) in 28 patients. Atrial tissues were obtained during mitral valve replacement. ANP-like immunoreactivity of the myocytes applied by the avidin-biotin peroxidase complex method was observed around the nuclei of the atrial myocytes. Electronmicroscopically, immunoreactivity was observed in atrial specific granules. Light-microscopically determined intensity of the immunoreactivity was classified into 4 grades and the intensity in 100 myocytes was expressed by adding the scores of each myocyte. Mean right atrial pressure was positively correlated with the activity score in RA (r = 0.80). Pulmonary capillary wedge pressure was not correlated with the score in LA. The score in RA was significantly higher than that in LA. The ANP level in RA investigated by RIA was also higher than that in LA. Histopathological findings such as myocyte hypertrophy, degeneration and interstitial fibrosis were more severe in LA than in RA. In conclusion, longstanding atrial overloading, especially in LA, caused severe pathological damage, resulting in a smaller production of ANP. Much more ANP may be produced from RA in long-standing mitral valve disease.