F-18-FDG is the most widely validated PET tracer for the evaluation of atherosclerotic inflammation. Recently, F-18-NaF has also been considered a potential novel biomarker of osteogenesis in atherosclerosis. We aimed to analyze the association between inflammation and osteogenesis at different stages of atherosclerosis, as well as the interrelationship between these 2 processes during disease progression. Methods: Thirty-four myeloma patients underwent F-18-NaF and F-18-FDG PET/CT examinations. Lesions were divided into 3 groups (noncalcified, mildly calcified, and severely calcified lesions) on the basis of calcium density as measured in Hounsfield units by CT. Tissue-to-background ratios were determined from PET for both tracers. The association between inflammation and osteogenesis during atherosclerosis progression was evaluated in 19 patients who had at least 2 examinations with both tracers. Results: There were significant correlations between the maximum tissue-to-background ratios of the 2 tracers (Spearman r = 0.5 [P < 0.01]; Pearson r = 0.4 [P < 0.01]) in the 221 lesions at baseline. The highest uptake of both tracers was observed in noncalcified lesions, but without any correlation between the tracers (Pearson r = 0.06; P = 0.76). Compared with noncalcified plaques, mildly calcified plaques showed concordant significantly lower accumulation, with good correlation between the tracers (Pearson r = 0.7; P < 0.01). In addition, enhanced osteogenesis- derived F-18-NaF uptake and regressive inflammation-derived F-18-FDG uptake were observed in severely calcified lesions (Pearson r - 0.4; P < 0.01). During follow-up, increased calcium density and increased mean F-18-NaF uptake were observed, whereas mean F-18-FDG uptake decreased. Most noncalcified (86%) and mildly calcified (81%) lesions and 47% of severely calcified lesions had concordant development of both vascular inflammation and osteogenesis. Conclusion: The combination of F-18-NaF PET imaging and F-18-FDG PET imaging promotes an understanding of the mechanism of plaque progression, thereby providing new insights into plaque stabilization.