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Introduction Interstitial lung disease (ILD) is a major cause of morbidity and mortality in systemic sclerosis (SSc), yet its course is highly variable and challenging to predict. We recently showed that baseline 68Ga-FAPI positron emission tomography/computer tomography (FAPI-PET/CT) findings associate with forced vital capacity (FVC) deterioration during follow up, after adjusting for baseline FVC and extent of ILD on high-resolution computer tomography (HRCT) in an exploratory cohort. Here we aimed to confirm these results in a larger SSc-ILD cohort. Moreover, we aimed to analyze how 68Ga-FAPI uptake associates with known clinical predictors of ILD progression.Material and Methods Eighty-eight patients with HRCT-confirmed SSc-ILD underwent FAPI-PET/CT. Clinical and laboratory data, including disease duration, history of arthritis and gastroesophageal reflux disease (GERD), 6-minute-walking distance (6MWT), modified Rodnan Skin Score (MRSS), anti-Scl70-autoantibody positivity and c-reactive protein (CRP), were recorded at the time of imaging. Pulmonary function tests (PFTs) were performed at the initial assessment and during routine follow-up visits. The longitudinal association between baseline 68Ga-FAPI uptake and changes in FVC was analyzed using generalized linear mixed-effects models. ILD progression was defined as a FVC decline of five percent or more assessed five years after FAPI-PET/CT. A binary classifier for ILD progression (progression vs. non-progression) was developed using the CatBoost algorithm.Results 68Ga-FAPI uptake volume normalized to lung volume was independently associated with accelerated decline in FVC (-294.18, 95% CI -476.83 to -111.53; p=0.002) in longitudinal mixed-effects models adjusted for clinical and serological covariates. A CatBoost model incorporating the FAPI/PET CT findings, age, disease duration, history of arthritis, GERD, MRSS, anti-Scl70-autoantibody positivity and CRP value at baseline predicted SSc-ILD progression with AUC of 0.90 in the test set. This model achieved 90% sensitivity and 96% specificity, with 68Ga-FAPI uptake volume normalized to lung volume emerging as the strongest predictor, outperforming established clinical and serological predictors of ILD progression.Conclusions 68Ga-FAPI uptake demonstrated superior predictive value compared with conventional clinical and serological risk factors, highlighting its potential as a prognostic biomarker for early risk stratification and personalized management in SSc-ILD.