Background— 18F-Sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) are promising novel biomarkers of disease activity in aortic stenosis. We compared 18F-NaF and 18F-FDG uptake with histological characterization of the aortic valve and assessed whether they predicted disease progression. Methods and Results— Thirty patients with aortic stenosis underwent combined positron emission and computed tomography using 18F-NaF and 18F-FDG radiotracers. In 12 patients undergoing aortic valve replacement surgery (10 for each tracer), radiotracer uptake (mean tissue/background ratio) was compared with CD68 (inflammation), alkaline phosphatase, and osteocalcin (calcification) immunohistochemistry of the excised valve. In 18 patients (6 aortic sclerosis, 5 mild, and 7 moderate), aortic valve computed tomography calcium scoring was performed at baseline and after 1 year. Aortic valve 18F-NaF uptake correlated with both alkaline phosphatase ( r =0.65; P =0.04) and osteocalcin ( r =0.68; P =0.03) immunohistochemistry. There was no significant correlation between 18F-FDG uptake and CD68 staining ( r =−0.43; P =0.22). After 1 year, aortic valve calcification increased from 314 (193–540) to 365 (207–934) AU ( P <0.01). Baseline 18F-NaF uptake correlated closely with the change in calcium score ( r =0.66; P <0.01), and this improved further ( r =0.75; P <0.01) when 18F-NaF uptake overlying computed tomography–defined macrocalcification was excluded. No significant correlation was noted between valvular 18F-FDG uptake and change in calcium score ( r =−0.11; P =0.66). Conclusions— 18F-NaF uptake identifies active tissue calcification and predicts disease progression in patients with calcific aortic stenosis. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01358513.