Background Minimally invasive transforaminal lumbar interbody fusion (MIS TLIF) for lumbar spondylolisthesis allows for the surgical treatment of back/leg pain while minimizing tissue injury and accelerating the patient's recovery. Although previous results have shown shorter hospital stays and decreased intraoperative blood loss for MIS versus open TLIF, short- and long-term outcomes have been similar. Therefore, we performed comparative effectiveness and cost-utility analysis for MIS versus open TLIF. Methods A total of 100 patients (50 MIS, 50 open) undergoing TLIF for lumbar spondylolisthesis were prospectively studied. Back-related medical resource use, missed work, and quality-adjusted life years were assessed. Cost of in-patient care, direct cost (2-year resource use × unit costs based on Medicare national allowable payment amounts), and indirect cost (work-day losses × self-reported gross-of-tax wage rate) were recorded, and the incremental cost-effectiveness ratio was calculated. Results Length of hospitalization and time to return to work were less for MIS versus open TLIF ( P  = 0.006 and P  = 0.03, respectively). MIS versus open TLIF demonstrated similar improvement in patient-reported outcomes assessed. MIS versus open TLIF was associated with a reduction in mean hospital cost of $1758, indirect cost of $8474, and total 2-year societal cost of $9295 ( P  = 0.03) but similar 2-year direct health care cost and quality-adjusted life years gained. Conclusions MIS TLIF resulted in reduced operative blood loss, hospital stay and 2-year cost, and accelerated return to work. Surgical morbidity, hospital readmission, and short- and long-term clinical effectiveness were similar between MIS and open TLIF. MIS TLIF may represent a valuable and cost-saving advancement from a societal and hospital perspective.