99mTc-pyrophosphate imaging has emerged as an important non-invasive method to diagnose transthyretin cardiac amyloidosis (ATTR-CM). Quantitation of 99mTc-pyrophosphate activity, on SPECT images, could be a marker of ATTR-CM disease burden. We assessed the diagnostic accuracy and clinical significance of 99mTc-pyrophosphate quantitation. Patients who underwent 99mTc-pyrophosphate imaging for suspected ATTR-CM were included. Using SPECT images, radiotracer activity in the myocardium was calculated using cardiac pyrophosphate activity (CPA) and volume of involvement (VOI), with thresholds for abnormal activity derived from LVBP activity. Diagnostic accuracy was assessed using area under the receiver operating characteristic curve (AUC). In total, 124 patients were identified, mean age 73.9 ± 11.4, with ATTR-CM diagnosed in 43 (34.7%) patients. CPA had the highest diagnostic accuracy (AUC .996, 95% CI .987-1.00), and was significantly higher compared to the Perugini score (AUC .952, P = .016). In patients with ATTR-CM, CPA was associated with reduced left ventricular ejection fraction (adjusted odds ratio 1.28, P = .035) and heart failure hospitalizations (adjusted hazard ratio 1.29, P = .006). Quantitative assessment of myocardial radiotracer activity with CPA or VOI have high diagnostic accuracy for ATTR-CM. Both measures are potential non-invasive markers to follow progression of disease or response to therapy.