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Objective: To compare the clinical and radiological outcomes of minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) and traditional open transforaminal lumbar interbody fusion (OPEN-TLIF) in the treatment of two-level lumbar degenerative diseases. Methods: The clinical data of 112 patients were retrospectively analyzed, and were divided into an MIS-TLIF group and OPEN-TLIF group. The operative time, intraoperative fluoroscopy, blood loss, postoperative drainage volume, bed rest time, the content of creatine kinase(CK) and complications, were recorded. VAS score and ODI index were used to evaluate clinical efficacy. Bridwell grading was used to evaluate postoperative interbody fusion. Screw position was evaluated by Rao grading. Results: Compared with the OPEN-TLIF group, the MIS-TLIF group had longer operation times, more intraoperative fluoroscopy times, but shorter postoperative bed times (p < 0.05). There were no significant differences in blood loss, postoperative drainage and postoperative CK content between the two groups (p > 0.05). There was no difference in VAS score and ODI index during the follow-up (p > 0.05). There was no significant difference in the interbody fusion rate between the two groups (p > 0.05). There was no significant difference in the distribution of type A screws, but the type B screw in the MIS-TLIF group was higher (p < 0.05). There was no difference in the incidence of complications between the two groups (p > 0.05). Conclusion: The postoperative quality of life score and radiological outcomes of the two types of surgery in two-level lumbar degenerative diseases was similar, and there was no significant difference in muscle injury and complications, but the operation time and intraoperative radiation exposurewere higher than in the OPEN-TLIF group, and the pedicle screws were more likely to deviate laterally out of the vertebral body. Therefore, OPEN-TLIF is recommended for patients with lumbar degenerative diseases of two segments.