Objective Validated methods for screening and early diagnosis of scleroderma-associated interstitial lung disease (SSc-ILD) are needed. In this study, we evaluated the performance of pulmonary function tests (PFTs) compared to high resolution computer tomography of the chest (HRCT) for the detection of SSc-ILD in clinical practice and aimed to identify predictors of functionally-occult, but HRCT-significant lung involvement. Methods Prospectively enrolled SSc patients were assessed following the EUSTAR standards, including PFTs and HRCT. The images were blindly evaluated by two experienced radiologists. The performance parameters of PFTs for the diagnosis of SSc-ILD were calculated. Predictors of significant ILD in HRCT in patients with normal FVC were identified through logistic regression. Results 64/102 (63.0%) patients showed significant ILD on HRCT, while only 27/102 (26.0%) had an FVC<80% and 54/102 (53.0%) had a decrease in at least one PFT. 40/64 (62.5%) patients with significant ILD on HRCT had a normal FVC, translating into a high false negative rate. Notably, 5/40 (6.0%) of patients with normal FVC had severe, functionally-occult lung fibrosis, 2 of these having all PFTs in normal limits. The false negative cases had more frequently anti-Scl-70 antibodies and diffuse SSc and less frequently anti-centromere antibodies (ACA) compared to ILD-free patients. Conclusion The derived evidence-based data reveal a high risk of missing the detection of significant SSc-ILD when relying solely on PFTs. More comprehensive screening algorithms for the early detection are warranted. Particularly, additional imaging investigations should be considered in ACA negative patients with normal FVC for the early detection of SSc-ILD. This article is protected by copyright. All rights reserved.