The goal of this study was to demonstrate whether increased 18F-fluoride uptake lesions on positron emission tomography (PET) scan can predict new syndesmophyte development in patients with ankylosing spondylitis (AS). In 12 AS patients, 18F-fluoride PET and magnetic resonance imaging (MRI) was performed at baseline, and radiography was performed at baseline and the 2-year follow-up. The following data were recorded: the presence of increased 18F-fluoride uptake lesions on PET defined as an uptake greater than the uptake in the adjacent normal vertebral body; acute (type A) and advanced (type B) corner inflammatory lesions (CILs) and fat lesions on MRI; and syndesmophytes on radiography. Of 231 anterior vertebral corners without syndesmophyte at baseline, 13 type A CILs (5.5%), 2 type B CILs (0.9%), and 20 fat lesions (8.7%) on MRI and six increased fluoride uptake lesions (2.6%) on PET were observed. At the 2-year follow-up, 16 new syndesmophytes (6.9%) in eight AS patients (66.7%) occurred. New syndesmophytes developed significantly more frequently in anterior vertebral corners with increased 18F-fluoride uptake lesions (50%) or fat lesions (25%) at baseline than in those without such lesions (5.8 and 5.2%; p = 0.005 and p = 0.007, respectively). After adjusting confounding factors, baseline increased 18F-fluoride uptake lesions was independently associated with new syndesmophytes development (OR 13.8, 95% CI 1.5-124.3, p = 0.019). Fat lesions were also associated with new syndesmophytes formation. Our data suggest that 18F-fluoride PET may be applied to identify AS patients with high risk of future syndesmophyte formation.