Background Positron emission tomography (PET) using ¹⁸ F-sodium fluoride ( ¹⁸ F-fluoride) to detect microcalcification may provide insight into disease activity in coronary atherosclerosis. This study aimed to investigate the relationship between ¹⁸ F-fluoride uptake and progression of coronary calcification in patients with clinically stable coronary artery disease. Methods Patients with established multivessel coronary atherosclerosis underwent ¹⁸ F-fluoride PET-computed tomography angiography and computed tomography calcium scoring, with repeat computed tomography angiography and calcium scoring at one year. Coronary PET uptake was analyzed qualitatively and semiquantitatively in diseased vessels by measuring maximum tissue-to-background ratio. Coronary calcification was quantified by measuring calcium score, mass, and volume. Results In a total of 183 participants (median age 66 years, 80% male), 116 (63%) patients had increased ¹⁸ F-fluoride uptake in at least one vessel. Individuals with increased ¹⁸ F-fluoride uptake demonstrated more rapid progression of calcification compared with those without uptake (change in calcium score, 97 [39–166] versus 35 [7–93] AU; P <0.0001). Indeed, the calcium score only increased in coronary segments with ¹⁸ F-fluoride uptake (from 95 [30–209] to 148 [61–289] AU; P <0.001) and remained unchanged in segments without ¹⁸ F-fluoride uptake (from 46 [16–113] to 49 [20–115] AU; P =0.329). Baseline coronary ¹⁸ F-fluoride maximum tissue-to-background ratio correlated with 1-year change in calcium score, calcium volume, and calcium mass (Spearman ρ=0.37, 0.38, and 0.46, respectively; P <0.0001 for all). At the segmental level, baseline ¹⁸ F-fluoride activity was an independent predictor of calcium score at 12 months ( P <0.001). However, at the patient level, this was not independent of age, sex, and baseline calcium score ( P =0.50). Conclusions Coronary ¹⁸ F-fluoride uptake identifies both patients and individual coronary segments with more rapid progression of coronary calcification, providing important insights into disease activity within the coronary circulation. At the individual patient level, total calcium score remains an important marker of disease burden and progression. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02110303.