OBJECTIVE: To evaluate the interaction between smoking status and operative approach following esophagectomy on perioperative outcomes. METHODS: Patients undergoing esophagectomy for esophageal cancer between January 1, 2009, and December 31, 2022, were identified from the STS-GTSD database and divided into 6 groups based on smoking status-never (NS), former (FS), or current (CS)-and surgical approach-minimally invasive (MIE) or open (OpenE). Primary outcomes were respiratory complications, operative mortality, major morbidity, and composite major morbidity and mortality. RESULTS: The final study population comprised 27,373 patients (28.3% NS, 68.0% FS, and 13.7% CS) from 295 hospitals. Most cases were OpenE (58.1%), but the proportion of MIE increased from 19.2% in 2009 to 56.3% in 2022. Multivariable analysis showed that (1) risk-adjusted operative mortality was decreased only in never-smokers who underwent MIE (MIE-NS: adjusted odds ratio [aOR], 0.61
95% confidence interval [CI], 0.45-0.82), and
(2) there were no significant differences in mortality among the groups compared to the reference OpenE-NS group. Respiratory complications, major morbidity, and composite mortality and morbidity outcomes showed similar smoking and surgical approach effects. All outcomes were worse in smokers irrespective of approach, and within the same smoking status group, AORs for respiratory complications and morbidity were slightly lower in MIE versus OpenE, but these differences were nonsignificant. CONCLUSIONS: Respiratory complications and other major morbidity outcomes following esophagectomy are substantially worsened by smoking history, particularly in current smokers. Among NS, MIE is associated with reduced operative mortality.