Cardiac amyloidosis may be asymptomatic or an important cause of progressive heart failure and refractory arrhythmia. To identify the morphologic markers of clinically significant cardiac amyloidosis, we analyzed the hearts of 47 patients with autopsy-proven cardiac amyloidosis (21 with primary amyloidosis [AL] and 26 with senile cardiac amyloidosis [SCA]) histologically for the extent and pattern of amyloid deposits. The extent of amyloid deposition was graded 1 through 4, corresponding with less than 10%, 10 to 25%, 26 to 50%, and more than 50% histologic involvement of the myocardium, respectively. The pattern of deposits was classified as nodular, perifiber, or mixed type, and the presence or absence of vascular involvement was determined. The hearts with primary amyloidosis showed predominantly high-grade deposits (76% grades 3 and 4), a perifiber (65%) or mixed (30%) pattern of deposits, and frequent (90%) vascular involvement. The hearts with senile cardiac amyloidosis tended to have low-grade deposits (62% grades 1 and 2), a nodular pattern (92%) of deposits, and infrequent (4%) vascular involvement. Clinically significant cardiac amyloidosis was associated with grade 2 or greater amyloid deposits in the heart and with involvement of intramyocardial arterioles.