Chylothorax after lobectomy is common, lacking reliable preventive measures. Octreotide is widely used for treatment of chyle leakage, but its role in preventing chylothorax has not been estimated. The aim of this study was to evaluate whether prophylactic octreotide could reduce the incidence of postoperative chylothorax.Patients who underwent lobectomy for lung cancer from January 2016 to September 2018 were retrospectively reviewed. The cases in prophylactic group received octreotide 1 day before the surgery until removal of chest tubes, while those in the control group did not use it unless the diagnosis of chylothorax.A total of 379 patients were enrolled, with 190 patients in control and 189 cases in prophylactic group. Octreotide was well tolerated in patients who received this agent. No 30-day mortality was indicated. Seven cases in control (3.7%, 7/190) and 3 cases in prophylactic group (1.6%, 3/189) with chylothorax were observed (P = .337). The patients in prophylactic group showed shorter duration of chest drainage ([3.6 ± 1.6] days vs [4.1 ± 2.0] days, P = .006) and reduced drainage volume ([441.8 ± 271.1] mL vs [638.7 ± 463.3] mL, P < .001). In addition, they showed similar stations and numbers of dissected lymph nodes, surgery-related complications, and postoperative hospital stay. Besides, 11 (5.8%, 11/190) patients in control and 6 (3.2%, 6/189) cases in the prophylactic group were readmitted for pleural effusion needing reinsertion of chest tubes (P = .321). Moreover, multivariable logistic analysis showed that induction therapy (odds ratio [OR] =12.03; 95% confidence interval [CI] 3.15-46.03, P < .001) was a risk factor, while high-volume experience of the surgeon (OR = 0.23; 95% CI 0.06-0.97, P = .045) was a preventive factor of surgery-related chylothorax. Additionally, prophylactic octreotide (OR = 0.18; 95% CI 0.11-0.28, P < .001) and perioperative low-fat diet (OR = 0.46; 95% CI 0.29-0.73, P = .001) were negatively associated with the drainage volume of pleural effusion. Furthermore, high-volume experience of the surgeon (OR = 6.03; 95% CI 1.30-27.85, P = .021) and induction therapy (OR = 8.87; 95% CI 2.97-26.48, P < .001) were risk factors of unplanned readmission.Prophylactic octreotide does not reduce the incidence of postoperative chylothorax or unplanned readmission following anatomic lobectomy. The routine application of octreotide should not be recommended. High-quality trials are required to validate these findings.