Retrospective case-control study.To compare minimally invasive transforminal lumbar interbody fusion (MIS-TLIF) and traditional open TLIF in the treatment of 2-segment lumbar degenerative diseases.In recent years, minimally invasive surgery (MIS) has been widely used compared with traditional open TLIF techniques, but owing to differences in research factors, MIS-TLIF and open TLIF remain controversial in the treatment of 2-level lumbar degenerative diseases.Patients who underwent 2-level MIS-TLIF (n=222) or traditional open TLIF (n=214) for lumbar degenerative disease were included. Demographics, intraoperative metrics, perioperative outcomes, imaging metrics, and functional evaluations [VAS, ODI, and SF-36; including minimal clinically important difference (MCID) achievement for VAS/ODI] were systematically compared between the MIS-TLIF and open TLIF cohorts.Patients who underwent MIS-TLIF had a significantly lower volume of blood loss (176.2±30.4 mL vs. 396.4±59.7 mL), lower postoperative drainage (102.6±22.6 mL vs. 164.4±26.9 mL), shorter bed rest time (3.3 d vs. 4.7 d), longer operative time (201.4±17.6 min vs. 147.7±16.0 min), and greater fluoroscopy time (45.3±6.3 s vs. 14.0±2.3  s) than those who underwent open TLIF. Significant clinical improvement was observed in terms of the VAS, ODI, and SF-36 scores between the preoperative evaluation and the final follow-up. Compared with the O-TLIF cohort, the MIS-TLIF cohort demonstrated superior long-term functional recovery, with significantly greater improvements in the ODI (81.1% vs. 51.4%, P<0.0001) at the 24-month follow-up.Both MIS-TLIF and open TLIF are effective approaches for the treatment of 2-level lumbar degenerative diseases. MIS-TLIF results in superior long-term functional and pain relief. The procedural choice should align with the physical condition of patients and surgeons' clinical experience.Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.