Spine fusion surgery in osteoporosis remains controversial because it is related to a high incidence of osteoporosis-related complications, such as cage nonfusion, pedicle screw loosening, and new vertebral compression fractures (VCFs). To treat 2-level degenerative lumbar disease in osteoporosis patients as an effective and safe surgical treatment for long-term results using minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF). We retrospectively assessed 12 patients with osteoporosis who underwent MIS-TLIF on L4 and L5 between 2011 and 2012 to assess the clinical and radiographic results for 2-level lumbar degenerative spine disease. All patients were followed-up for at least 2 yr after surgery and assessed by using X-ray. Basic patient data and clinical and radiological outcomes were collected and analyzed. Of all 12 patients, 11/12 (91.6%) and 1/12 (8.3%) demonstrated cage fusion and cage subsidence, respectively. Pedicle screw loosening was found in 1/12 (8.3%) patients. The P-values calculated using the F-test for changes in the vertebral body height pre- and postoperation in L3, L4, and L5 were .69, .87, and .39, respectively. The data revealed no significant variants of new VCFs. MIS-TLIF provided a high cage fusion rate and low pedicle screw loosening rate in patients with osteoporosis with 2-level degenerative spine disease. Furthermore, no new VCFs were found in long-term follow-up. The clinical outcomes also demonstrated no significant difference compared with traditional open spine fusion surgery. Therefore, MIS-TLIF could be considered an effective and safe surgical treatment modality for 2-level degenerative spine disease in osteoporosis.