Histopathological and electrocardiographical (ECG) changes occur in the heart of C3H/HeN and C57BL/6 mice infected for 1 year with Trypanosoma cruzi clones Sylvio-X10/4 (X10/4), Miranda/78 (M/78), or Miranda/80 (M/80). Heart parasitism and a variable degree of inflammation occurred following infection with clones X10/4 or M/78 but not with M/80. Clone X10/4 caused more extensive myocardial inflammation and fibrosis than clone M/78. Myocardial fibrosis was more extensive in C3H than in C57 mice infected with clone X10/4. The normal ECG pattern of C3H mice is distinctly different from C57 mice. The PR intervals of mice infected with clone X10/4 > M/78 > M/80 ≊ controls. ECG abnormalities occurred more frequently in mice infected with clone X10/4 than in controls or mice infected with either M/78 or M/80 regardless of strain or sex and were generally more severe in C57 than in C3H infected with X10/4. First degree atrioventricular block occurred more frequently in C3H mice infected with clone X10/4 or M/78 and C57 mice infected with X10/4 than in all other groups. Complete atrioventricular dissociation occurred frequently in C57 mice infected with X10/4 and rarely in other mice. These results demonstrate that the myocardial response of mice to T. cruzi infection, both histological and electrophysiological, is modulated by both the mouse strain and the parasite isolate used.