Objective We aimed to analyse the effects of real-life immunomodulatory therapy with cyclophosphamide and rituximab for interstitial lung disease (ILD) in patients with systemic sclerosis (SSc-ILD), anti-synthetase syndrome (ASS-ILD), or Sjögren’s syndrome (SjS-ILD), in a single academic centre. Methods All inpatients with connective tissue diseases treated with intravenous bolus cyclophosphamide or rituximab were identified from the Medical Centre records. Information on patient characteristics, chest CT results, pulmonary function tests, therapies, and severe adverse events, were extracted from inpatient and outpatient records. Results Intravenous cyclophosphamide bolus therapy was used in 27 patients with SSc. Cyclophosphamide improved forced vital capacity (FVC) by more than 10% in 4 patients and stabilised it at -0.4% to +3.25% in 8. Rituximab constituted a rescue therapy in 14 SSc patients, and was used for treating 4 patients with ASS-ILD, 2 patients with SjS-ILD and one additional SSc-ILD patient. Rituximab led to FVC improvements of at least 5% in 8 patients and to stabilisation in another 6. 6 patients under cyclophosphamide and 8 patients under rituximab experienced severe adverse events. 8 of the 34 patients died, half of them from causes potentially related to therapy. Conclusion In this subset of severely sick patients with connective tissue diseases, cyclophosphamide and/or rituximab led to improvement in 12 patients, and stabilisation was seen in 14. Despite the new options with nintedanib, immunomodulation remains a relevant therapeutic modality for ILD associated with connective tissue disease.