Fourteen patients with biopsy-proved systemic amyloidosis underwent noninvasive cardiac testing to assess the presence and severity of cardiac amyloidosis. There was a clear tendency for electrocardiographic voltage to be low (sum of S wave in lead V1 plus R wave in lead V5 or V6 [SV1 + RV5 or V6] = 14.6 +/- 4.8 mm; normal range 15 to 35) and echocardiographic muscle cross-sectional area to be increased (11.4 +/- 2.7 cm2/m2; normal range 6 to 10). When the electrocardiographic or the echocardiographic data were examined individually, and especially when they were compared and contrasted with similar measurements from patients with pericardial disease (n = 8) or aortic valve disease (n = 24), it was apparent that the electrocardiogram and the echocardiogram had limited specificity in the diagnosis of amyloidosis. However, when the analysis combined these two techniques, a distinctive pattern emerged. There was an inverse correlation between voltage and muscle cross-sectional area (r = -0.79) in patients with amyloidosis; moreover, marked derangement of the voltage/cross-sectional area relation was associated with clinical symptoms and mortality. In addition, patients with amyloidosis and cardiac symptoms had abnormal left ventricular chamber radius to wall thickness ratios, consistent with infiltration of the myocardium as the primary abnormality in cardiac amyloidosis.