In the largest study of its kind to date, involving 427 patients from two cohorts, the performance and optimal positioning of candidate serum biomarkers of interstitial lung disease (ILD) in systemic sclerosis (SSc) was assessed. SP-D, KL-6 and CCL18 performed best as biomarkers for ILD diagnosis, lung fibrosis severity and ILD progression, respectively. A matrix model that combined baseline concentrations of SP-D and anti-topoisomerase I antibody positivity could accurately stratify patients on the basis of their risk of fibrosis, whereas a model that incorporated CCL18 levels could stratify patients with SSc-ILD on the basis of their risk of ILD progression.