Objective To explore the clinical value of contrast-enhanced ultrasound-guided biopsy in the early diagnosis of pleural tuberculoma. Methods A total of 87 patients were recruited, who were admitted to Shanghai Pulmonary Hospital affiliated to Tongji University from Jan. 2017 to Jan. 2018 and were diagnosed to have pleural tuberculoma based on clinical indication and imaging. All patients underwent contrast-enhanced ultrasonography and ultrasound-guided biopsy, and then the samples were sent for pathological examination, acid-fast bacilli culture and polymerase chain reaction for Mycobacterium tuberculosis. The clinical data of the patients were collected and the results of contrast-enhanced ultrasound, final diagnostic positive rate and adverse reactions were statistically analyzed. Results The success rate of contrast-enhanced ultrasound-guided biopsy of 87 patients was 100%, among which 70 cases were diagnosed with tuberculosis, 7 with maligmant tumors, 4 with other infection diseases, and 6 cases obtained negative results (confirmed by diagnostic anti-tuberculosis and thoracoscopic biopsy, 5 with tuberculosis and 1 with pleural mesothelioma). Seventy-five of 87 cases were eventually diagnosed with tuberculosis, of which 70 (93.33%) were diagnosed by contrast-enhanced ultrasound-guided biopsy. The intensity of contrast-enhanced ultrasound was an important differential factor for pleural tuberculoma and malignant tumor; low enhancement mainly existed in the pleural tuberculoma (66/75), and high enhancement mainly existed in the malignant tumor (4/7). Hemorrhage and/or hemoptysis occurred in 5 cases during the puncture, pleural reaction occurred in 3 cases, and all of them was relieved after symptomatic treatment. Conclusion Contrast-enhanced ultrasound-guided biopsy has a high value for the early diagnosis of pleural tuberculoma, with high positive rate, small trauma and good reproducibility, and is worthy of clinical promotion.