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Objectives To characterise the aetiological spectrum of thoracic granulomatous diseases and identify diagnostic features that facilitate differentiation among causes.Design Retrospective multicentre observational study.Setting Two tertiary hospitals in south-central China. Patient data were consecutively enrolled from 1 June 2020 to 30 June 2023.Participants Of 2486 patients with pathologically confirmed thoracic granulomas initially identified, exclusions were applied for specimens outside the lung/pleura/mediastinum (579), incomplete demographic/imaging/pathology data (280) or lack of follow-up (231). A total of 1396 patients met all criteria (853 from hospital 1 and 543 from hospital 2) and were included in the final analysis.Primary and secondary outcome measures We quantified the aetiologic distribution of thoracic granulomatous diseases and examined age-stratified/lesion-location differences in aetiologic patterns. We also evaluated associations between histopathological features and specific aetiologies and compared the diagnostic accuracy across sampling modalities.Results Among the 1396 enrolled cases, a confident, probable and uncertain diagnosis was made in 1086 cases, 307 cases and 84 cases. Infectious granulomas predominated (89.4%; 1248/1396), with tuberculosis comprising 87.8% (1096/1248) of infectious cases. Among non-infectious granulomas, sarcoidosis was most common (65.8%; 50/76). Patients aged ≥60 years had a higher proportion of infectious granulomas than younger groups (≥60 years: 389/422; 40–60 years: 633/714; <40 years: 226/260; p=0.044). Fungal granulomas were more frequent in those aged 40–59 years (10.9% of infectious granulomas). Diagnostic accuracy was highest for surgical biopsy (93.5%, 288/305), followed by thoracoscopy (92.3%, 108/117) and transbronchial lung biopsy (74.7%, 510/683). Necrosis was present in 88.6% of granulomas; positive special stains were strongly associated with fungal infection.Conclusions Most thoracic granulomas arise from mycobacterial or fungal infection, while sarcoidosis is the leading non-infectious cause. Thoracoscopy and surgical biopsy show superior diagnostic yields, and special staining aids differentiation of fungal aetiologies. Findings support a multidisciplinary approach to improve diagnostic accuracy.