Background: Lateral recess stenosis (LRS) is a common degenerative disease in the elderly. Since the rise of comorbidity is associated with the increasing age, the percutaneous endoscopic lumbar decompression is advocated. The objective of this study was to compare the clinical outcomes of percutaneous endoscopic lumbar decompression in LRS via TESSYS or TESSYS-ISEE approach. Methods: A total of 45 and 42 consecutive patients with limp or radiculopathy symptoms underwent percutaneous endoscopic lumbar decompression using transforaminal endoscopic spine system (TESSYS) and TESSYS-ISEE, respectively. The radiation exposure and operation time, time to return to work, and complications were compared between two groups. Their clinical outcomes were evaluated with visual analogue scale (VAS) leg pain score, VAS back pain score, Oswestry Disability Index (ODI) and Modified MacNab’s criteria. Results: The average values of radiation exposure and operative time in TESSYS group were significantly higher than those in TESSYS-ISEE group (P<0.05). The postoperative VAS and ODI scores in both groups were significantly improved compared with before the operation (P<0.05). In addition, the VAS score of the leg and ODI score in the TESSYS-ISEE group were significantly lower than those in TESSYS group at 1 week follow-up (P<0.05). The good-to-excellent rates of the TESSYS and TESSYS-ISEE group were 88.89 and 90.48%, respectively, whereas the complication occurrence rates were 6.67 and 4.76% in TESSYS and TESSYS-ISEE groups, respectively. Conclusions: TESSYS-ISEE can be applied to treat LRS safely and effectively with short radiation exposure and operation time. This approach was comparable to the TESSYS approach with improved VAS leg pain and ODI score in short period after operation. However, potential complications and risks still needs to be considered.