Background: With a steep increase in the number of instrumented spinal fusion procedures, there is a need for comparative data to develop evidence based treatment recommendations. Currently, the available data on cost and clinical effectiveness of the two most frequently performed surgeries for lumbar spondylolisthesis, transforaminal lumbar interbody fusion (TLIF) and posterior lumbar interbody fusion (PLIF), are not sufficient. Therefore, current guidelines do not advise which is the most appropriate surgical treatment strategy for these patients. Non-randomized studies comparing TLIF and PLIF moreover suggest that TLIF is associated with fewer complications, less blood loss, shorter surgical time and hospital duration. TLIF may therefore be more cost-effective. The results of this study will provide knowledge on short- and long-term clinical and economical effects of TLIF and PLIF procedures, which will lead to recommendations for treating patients with lumbar spondylolisthesis. Methods: Multicenter blinded Randomized Controlled Trial (RCT; blinding for the patient and statistician, not for the clinician and researcher). A total of 144 patients over 18 years old with symptomatic single level lumbar degenerative, isthmic or iatrogenic spondylolisthesis whom are candidates for LIF (lumbar interbody fusion) surgery through a posterior approach will be randomly allocated to TLIF or PLIF. The study will consist of three parts: 1) a clinical effectiveness study, 2) a cost-effectiveness study, and 3) a process evaluation. The primary clinical outcome measures are: change in disability measured with Oswestry Disability Index (ODI) and change in quality adjusted life years (QALY) measured with EQ-5D-5L. Secondary clinical outcome measures are: Short Form (36) Health Survey (SF-36), VAS back pain, VAS leg pain, Hospital Anxiety Depression Scale (HADS), complications, productivity related costs (iPCQ) and medical costs (iMCQ). Measurements will be carried out at five fixed time points (pre-operatively and at 3, 6, 12 and 24 months). Discussion: It is hypothesized that TLIF, compared to PLIF, has similar clinical outcome or is possibly better in reducing disability. Moreover, direct medical costs are expected to be lower due to less surgical morbidity, shorter hospital stay and shorter surgical time. Indirect costs are assumed to be lower for TLIF as well, because we suspect less working days are lost. Currently, prospective data comparing clinical and cost-effectiveness of both techniques are not available. Therefore, in clinical practice both techniques are used and the choice for technique is greatly based on surgeon's preference. The demand for spinal fusion surgery has risen steeply over the last 10 years and is expected to increase even further in the near future. As a result, the burden on society (and the working population) will increase. In case our hypothesis is confirmed, treatment guidelines will be adapted, and TLIF will be recommended as first choice surgical treatment of lumbar spondylolisthesis. Ultimately this will lead to reduction of (direct and indirect) costs and better clinical outcome for spondylolisthesis patients eligible for instrumented spinal surgery.