Objective: To improve the recognition and diagnostic accuracy of pulmonary cryptococcosis through the comparative analysis of CT images and histopathology. Methods: A total of 53 patients with pulmonary cryptococcosis detected by chest CT scan, resected through video-assisted thoracoscopic surgery (VATS), and diagnosed by postoperative pathological analysis were included in our study from January 2010 to December 2019 in Huashan Hospital, Fudan University. By comparing the characteristics of CT and pathological images, the histological basis of the CT imaging changes of pulmonary cryptococcosis was analyzed. Results: The CT findings of pulmonary cryptococcosis were nodules in 49 cases, patches in 3 cases, mixed patchy and nodule in 1 case. The size of the lesions in 49 cases were less than 3 cm, of which 24 cases were less than 1 cm. In 45 cases, the distance from the lesion to the pleura was less than 1 cm. Fifty cases were high density or high- and low-density mixed shadows, and 3 cases were ground glass shadows. Vacuoles was found in 18 cases, lucid area, and air bronchogram sign in 4 cases, and cavitation in 3 cases, respectively. Twenty-four cases showed spiculation on the edge, and 13 cases showed lobulated edges. In 31 cases, the lesion was clearly demarcated from the surrounding lung tissue, and in 22 cases, the lesion was not clearly demarcated from the surrounding tissue, with halo sign/ground glass opacities, vascular cluster, and pleural indentation. Histological examination found that 49 cases of pulmonary cryptococcal lesions showed granulomatous inflammation, and 4 cases showed non-granulomatous histiocytic reaction. In the granulomatous lesions, there were 12 cases with coagulative necrosis, 3 cases with cavitation, 3 cases with abscess-formation and 1 case with “cryptococcus lake”-formation, 8 cases with residual alveoli and 3 cases with dilated bronchus inside lesions; 13 cases with organizing pneumonia, 4 cases with fibrous encapsulation and 4 cases with widened alveolar septum due to inflammation were found in the edge of lesions, respectively. Hemorrhage and edema in 18 cases, vascular dilation, entanglement, and penetration in 15 cases, and pleural traction in 10 cases were founded around lesions. Conclusion: The various histological features of pulmonary cryptococcosis lead to corresponding imaging changes. Understanding of the histological basis of CT imaging changes in pulmonary cryptococcus infection, combined with histological examination of puncture specimens, can avoid overdiagnosis of malignancy and reduce unnecessary surgical treatment.