Objective To analyze and compare the clinical features of patients with pulmonary involvement of Whipple disease and primary treated bacteriological negative pulmonary tuberculosis,so as to improve the recognition,diagnosis and differentiation ability of pulmonary involvement of Whipple disease．Methods Clinical features of Whipple disease with pulmonary involvement were investigated by retrospectively collecting 20 cases as a case group,comparing with 56 randomly selected patients with primary treated bacteriological negative pulmonary tuberculosis as a control group during the same period．Results The case group had a significantly higher proportion of older patients（>37 years）,acute or subacute disease courses than the control group （P<0.05）．On CT imaging,in terms of lesion distribution,the proportion of cases with lesions in the lower lobe was significantly more in the case group than in the control group（P<0.05）,and the ratio of cases with lesions in the upper lobe was considerably less than in the control group（P<0.05）．Regarding morphology,significantly more of the case group showed reticular lesions and interstitial pneumonia than the control group（P<0.05）．Significantly fewer of the case group showed cavities,fibrous bands,solid shadows,nodular shadows,tree-bud signs,and enlarged hilar lymph nodes than the control group（P<0.05）．No statistically significant differences existed between the two groups in gender,combined immunocompromising diseases,cough,sputum,fever,coughing up blood,arthralgia or diarrhea. At the same time,the differences of gender,combined immunocompromised disease,cough,sputum,fever,coughing up blood,arthralgia,and diarrhea were not statistically significant．The metagenomic sequencing of alveolar lavage fluid in the case group revealed Tropheryma whipplei as the sole pathogenic bacteria in 19 cases（95%）or the primary pathogenic bacteria in 1 case（5.00%,combined TB 1 sequence）．In contrast,metagenomic sequencing of alveolar lavage fluid in the control group detected Mycobacterium tuberculosis complex as the sole or primary pathogenic bacteria in 21 cases（37.5%）,TB-RNA（+）in 18 cases and TB-LAMP（+）in 15 cases．Conclusions Clinical presentation in Whipple disease can be of an acute or subacute course,preferably in middle-aged and older men,with fever or/and respiratory symptoms,either with or without diarrhea and arthralgia．Its pulmonary imaging dominates with reticular,interstitial pneumonia changes in the lower lungs,which can involve the lungs alone in the disease．At the same time,the clinical symptoms are highly similar to those patients with primary treated bacteriological negative pulmonary tuberculosis．Therefore,it is vital to complete bronchoscopy and metagenomic sequencing of alveolar lavage fluid as soon as possible for early and rapid diagnosis of this Whipple disease．Treatment with sensitive antibacterial drugs can result in significant improvement and save patients' lives．