Ten nuclei from the endomyocardial biopsies for each of the following 32 patients were examined by electron microscopy: seven patients before and then four and 24 hours after treatment with first-dose doxorubicin; seven patients before and four and 24 hours after treatment with first-dose doxorubicin plus N-acetyl cysteine; nine patients with doxorubicin induced cardiomyopathy; and nine patients with idiopathic congestive cardiomyopathy. Five criteria were used to semiquantitatively compare nuclei and nucleoli from each group. The most dramatic changes in nuclear and nucleolar morphology were seen four hours after doxorubicin administration. Nucleoli were smaller, contracted or segregated and contained fewer fibrillar centers and a collapsed or fragmented nucleolonema. The addition of N-acetylcysteine to treatment did not alter these results. By 24 hours, nuclei had returned to the pre-treatment status. Long-term doxorubicin therapy produced increased chromatin clumping and slightly contracted nucleoli. The idiopathic congestive cardiomyopathic nuclei differed significantly from these doxorubicin cardiomyopathic nuclei in the decreased amount of chromatin clumping and the increase in fibrillar centers and nucleonema pattern. It is concluded from this study that: (1) doxorubicin markedly alters the morphology of the human myocardial nucleus and nucleolus four hours after treatment, but these changes diminish by 24 hours; (2) N-acetylcysteine treatment fails to prevent these changes; and (3) the nuclei and nucleoli of chronic doxorubicin-induced cardiomyopathy differ significantly from other congestive cardiomyopathies, but do resemble changes seen four hours after the first dose of doxorubicin.