<p>Background</p><p>S1–L5 transdiscal screw fixation is a direct stabilization technique used for surgical treatment of high-grade (III–IV) L5–S1 spondylolisthesis. It has not been used for nonspondylolisthetic cases or in combination with an interbody cage (IC). This study aimed to develop a novel, direct S1–L5 sacrolumbar interbody fusion (SLIF) technique, a combination of IC and sacrolumbar transdiscal screw.</p><p>Methods </p><p>SLIF was tested in cadaveric, clinical, and finite element analysis settings. Three cadaveric lumbar spines were used to test the SLIF procedure before clinical application. Eight patients underwent the SLIF procedure. Clinical outcomes were evaluated by visual analog score for leg and back pain, short form 36, Oswestry disability index, and neurological examination. CT scans of the lumbar spine were used to assess the hardware placement and subsequent fusion. Finite element analysis was performed on a healthy human CT-based L5-S1 model. Intact segment, unilateral facetectomy and discectomy, SLIF, and transforaminal lumbar interbody fusion (TLIF) procedures were compared in terms of the range of motion (ROM), von Mises stress on hardware, and shear-induced directional deformity. Additionally, the same set of tests were conducted in an osteoporotic model.</p><p>Results</p><p>Excellent hardware placement was feasible in three cadavers and eight patients. Preoperative neurological deficits improved in all patients. Statistically significant improvements were obtained on all self-reported questionnaire scores. All patients developed solid, Bridwell grade I fusions. Biomechanical testing revealed similar outcomes for TLIF and SLIF regarding the ROM. However, the screw's von Mises stress and shear-induced directional deformity were low for SLIF of healthy and osteoporotic bone.</p><p>Conclusions </p><p>SLIF is a feasible, safe, and effective L5–S1 fusion option suitable for all clinical scenarios. It provides several biomechanical advantages, yielding excellent clinical outcomes.</p>