To explore the feasibility of mesangium or membrane anatomy theory in thoracolaparoscopic radical esophagectomy for esophageal cancer, 98 patients with esophageal cancer were enrolled including 45 patients in the mesoesophageal esophagectomy group and 53 patients in the non-mesoesophageal esophagectomy group. Thoracolaparoscopic radical esophagecotmy was technically successful in all patients. Compared the non-mesoesophageal group, the mesoesophageal group had significantly (P < 0.05) shorter surgical duration (211.9 ± 42.0 min vs. 282.0 ± 44.5 min), less blood loss during the procedure (68.9 ± 45.9 ml vs. 167.0 ± 91.4 ml), more harvested lymph nodes (25.9 ± 6.3 vs. 21.8 ± 7.3), shorter hospital stay after surgery (10.5 ± 2.5 d vs. 12.5 ± 4.2 d), shorter fasting time or quicker postoperative feeding time (7.3 ± 1.2 d vs. 9.5 ± 3.9 d), and quicker removal of the thoracic drainage tube after surgery (7.7 ± 2.0 d vs. 9.2 ± 4.1 d). The overall incidence of postoperative complications was 46.7% (21/45) in the mesoesophageal group, which was significantly (P = 0.02) fewer than that (69.8% or 37/53) of the non-mesoesophageal group (P = 0.020). During follow-up 20.6 ± 4.3 or 20.8 ± 3.4 months after esophagectomy, liver metastasis occurred in 1 case and lung metastasis in 1 in the mesoesophageal group, whereas liver metastasis occurred in 2 cases, mediastinal metastasis in 2, and anastomotic recurrence in 1 in the non-mesoesophageal group. The mesoesophageal group had significantly better physical function (81.9 ± 7.3 vs. 78.3 ± 7.6), social function (65.1 ± 7.1 vs. 56.2 ± 18.2), global health status (65.3 ± 10.1 vs. 58.7 ± 12.4), and pain improvement (29.5 ± 9.5 vs. 35.6 ± 10.6). The overall survival rate was 82.2% (37/45) in the mesoesophageal group and 71.7% (38/53) in the non-mesoesophageal group (P = 0.26). The disease-free survival rate was 77.8% (35/45) for the mesoesophageal group and 62.3% (33/53) for the non-mesoesophageal group (P = 0.13). In conclusion:, the mesangium or membrane anatomy theory can be used safely and effectively to guide thoracolaparoscopic radical esophagectomy for esophageal cancer, with advantages of shorter surgical time, less bleeding, more lymph node harvest, fewer complications, and faster postoperative recovery.