OBJECTIVE: The SENSCIS® trial demonstrated a significant reduction of lung function decline in patients with systemic sclerosis (SSc)-associated interstitial lung disease (SSc-ILD) treated with nintedanib, but no significant effect on health-related quality of life (HRQoL). To assess whether SSc/SSc-ILD severity and large changes in lung function correlate with HRQoL, a post-hoc analysis of SENSCIS®, aggregating treatment arms, was undertaken. METHODS: Patient-reported outcome (PRO) measures (St. George's Respiratory Questionnaire [SGRQ], Functional Assessment of Chronic Illness Therapy [FACIT]-Dyspnoea, and Health Assessment Questionnaire-Disability Index [HAQ-DI], incorporating the Scleroderma Health Assessment Questionnaire visual analogue scale [SHAQ VAS]) at baseline and week 52 were assessed for associations to SSc-ILD severity. RESULTS: At baseline and at week 52, forced vital capacity (FVC) <70% predicted was associated with worse PRO measure scores compared with FVC ≥70% predicted (week 52: SGRQ 45.1 vs 34.0 [p< 0.0001]; FACIT-Dyspnoea 48.9 vs 44.5 [p< 0.0001]; HAQ-DI 0.7 vs 0.6 [p< 0.0228]; SHAQ VAS breathing problems 3.6 vs 2.6 [p< 0.0001]). Patients with diffuse cutaneous SSc and other characteristics associated with SSc-ILD severity had worse PRO measure scores. Patients requiring oxygen or with >30% fibrosis on high-resolution computed tomography at baseline demonstrated worse PRO measure scores at week 52. After 1 year, patients with a major (>10%) improvement/worsening in FVC demonstrated corresponding improvement/worsening in SGRQ and other PRO measures, significant for the SGRQ symptom domain (p< 0.001). CONCLUSION: Severe SSc-ILD and major deteriorations in lung function have important impacts on HRQoL. Treatments that slow lung function decline and prevent severe SSc-ILD are important to preserve HRQoL. TRIAL REGISTRATION: clinicaltrials.gov, www.clinicaltrials.gov, NCT02597933.