This study aimed to assess the effectiveness of saline sealing in reducing the incidence of pneumothorax after a CT-guided lung biopsy. This was a retrospective case-control study of patients who underwent CT-guided biopsies for lung tumors using 18 G semiautomatic core needles in conjunction with 17 G coaxial needles. The patients were divided into two consecutive groups: a historical Group A (n = 111), who did not receive saline sealing, and Group B (n = 87), who received saline sealing. In Group B, NaCl 0.9% was injected through the coaxial needle upon its removal. The incidence of pneumothorax and chest tube insertion was compared between the two groups. Multivariate logistic regression was performed to verify the contribution of other pneumothorax risk factors. The study included 198 patients, with 111 in Group A and 87 in Group B. There was a significantly (p = 0.02) higher pneumothorax rate in Group A (35.1%, n = 39) compared to Group B (20.7%, n = 18). The difference regarding chest tube insertion was not significant (p = 0.1), despite a tendency towards more insertions in Group A (5.4%, n = 6), compared to Group B (1.1%, n = 1). Among the risk factors for pneumothorax, only the presence of emphysema (OR = 3.5, p = 0.0007) and belonging to Group A (OR = 2.2, p = 0.02) were significant. Saline sealing of the needle tract after a CT-guided lung biopsy can significantly reduce the incidence of pneumothorax. This technique is safe, readily available, and inexpensive, and should be considered as a routine preventive measure during this procedure.