Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterised by myofibroblast proliferation and abnormal extracellular matrix (ECM) accumulation in the lungs. Transforming-growth-factor (TGF)-β1 initiates key profibrotic signaling involving the SMADs pathway and the small heat shock protein αB-crystallin (HSPB5). TRIpartite Motif-containing 33 (TRIM33) has been reported to negatively regulate TGF-β/SMADs signaling but its role in fibrogenesis remains unknown. To elucidate the role of TRIM33 in IPF. TRIM33 expression was assessed in the lungs of IPF patients and rodent fibrosis models. Bone Marrow-derived Macrophages (BMDM), primary lung fibroblasts and 3D-lung tissue slices were isolated from -floxed mice and cultured with TGF-β1 or bleomycin (BLM). expression was then suppressed by adenovirus-Cre recombinase (AdCre). Pulmonary fibrosis was evaluated in hematopoietic-specific knock-out (KO) mice and in -floxed mice that received AdCre and BLM intratracheally. TRIM33 was overexpressed in alveolar macrophages and fibroblasts in IPF patients and rodent fibrotic lungs. inhibition in BMDM increased TGF-β1 secretion upon BLM treatment. Hematopoietic-specific -KO sensitised mice to BLM-induced fibrosis. In primary lung fibroblasts and 3D-lung tissue slices, -deficiency increased TGF-β1-downstream gene expression. In mice, AdCre- inhibition worsened BLM-induced fibrosis. , HSPB5 was able to bind directly to TRIM33, thereby diminishing its protein level and TRIM33/SMAD4 interaction. Our results demonstrate a key role of TRIM33 as a negative regulator of lung fibrosis. Since TRIM33 directly associates with HSPB5 which impairs its activity, inhibitors of TRIM33/HSPB5 interaction may be of interest in the treatment of IPF.