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Introduction Although most vasoactive-vasodilating drugs (VVDs) exert anti-fibrotic effects in pre-clinical studies, randomized controlled trials assessing their efficacy in systemic sclerosis-associated interstitial lung disease (SSc-ILD) showed mixed results. Therefore, we assessed the impact of VVDs on functional progression of SSc-ILD in an observational, real-life setting.Material and Methods We identified SSc patients with ILD on computed tomography, follow-up pulmonary function tests (PFTs) and treatment data in the EUSTAR database and excluded those with pulmonary hypertension on right heart catheterization or systolic pulmonary artery pressure on echocardiography>50mmHg. Exposure included endothelin-receptor antagonists, phosphodiesterase-5 inhibitors and prostanoids, administered for at least 3 months in the observation period.ILD progression within 12±3 months was defined as a decline in:Forced vital capacity (FVC)>=10%, or 5-9% with diffusion capacity for carbon oxide (DLCO) decline>=15%FVC >=5% or DLCO>=10%FVC>=10%FVC>=5%Otherwise as:D. Worsening of NYHA class.Generalized estimated equation mixed models were performed separately for each ILD progression outcome.Cox regression with time-dependent variables was applied for survival analysis, with death as outcome.All models included interaction terms (VVDs and digital ulcers – DU, VVDs and DLCO) and were adjusted for known risk factors for ILD progression, mortality and ongoing immunosuppression.Results Among 1950 SSc-ILD patients, progression was recorded in 13-42% of 5360 yearly visits. Exposure to VVDs varied from 10 to 25% of visits, with prostanoids being the most frequent.The interaction of prostanoids and DU was associated with progression A (p=0.057), B (p=0.028), C (p=0.006) and D (p=0.048). This translated into a protective association of prostanoids against PFT decline in patients without DU, compared to patients with DU.Additionally, prostanoids interacted significantly with DLCO, and this associated significantly with all progression definitions (A: p=0.022, B: p=0.003; C: p=0.001; D: p=0.023; E: p=0.010). Practically, higher DLCO values impacted positively on the effectiveness of prostanoids against ILD progression.Combining all effects, prostanoid significantly associated with less PFT progression when used in patients without DU and with DLCO>70%, while DLCO values >100% would be needed for prostanoids to exert similar effects in DU patients.In the survival analysis [178 deaths (15.6%), median follow-up 5.7 years], VVDs did not show any significant, independent impact on mortality.Conclusions Exposure to prostanoids is associated with lower risk of ILD progression in patients with mild vasculopathy. Given our positive preliminary results on short-term progression, but the lack of independent impact on mortality, further studies are needed.