Study Design.Retrospective cohort study.Objective.The aim of this study was to compare outcomes in patients undergoing 1-level transforaminal lumbar interbody fusion (TLIF) at L4-S1.Background.TLIF is frequently performed at L4-S1 to treat degenerative lumbar pathologies. However, the native alignment and biomechanics differ across L4-L5 and L5-S1, and there is limited data regarding comparative radiographic outcomes.Patients and Methods.Patients who underwent 1-level TLIF at L4-L5 or L5-S1 at a single academic institution were identified. Baseline demographics, procedural characteristics, change in postoperative spinopelvic alignment patient-reported outcome measures, and 2-year postoperative surgical complications were compared. Multivariate regression analyses, accounting for age, sex, Charlson Comorbidity Index, and body mass index, were also performed.Results.Across the 175 included patients, 125 had L4-L5 TLIF and 50 had L5-S1 TLIF. The mean age was 57.8 years, 56.6% were females, the mean Charlson Comorbidity Index was 0.9, and the mean follow-up was 26.7 months. In the hospital, the 2 cohorts were not statistically different with regard to estimated blood loss and length of stay. Two years postoperatively, multivariate linear regression analyses revealed that L5-S1 TLIF achieved 6.0 degrees higher correction in L4-S1 lordosis (P = 0.012) than L4-L5 TLIF. At the same time, however, L5-S1 patients undergoing TLIF experienced significantly higher rates of pseudoarthrosis (8.0% vs. 1.6%, P = 0.036) and subsequent spine surgery (18.0% vs. 7.2%, P = 0.034), specifically for pseudoarthrosis (6.0% vs. 0.0%, P = 0.006), with this cohort having 8.7 times higher odds of subsequent spine surgery for pseudoarthrosis (P = 0.015) than L4-L5 patients undergoing TLIF on multivariate logistic analyses. Patient-reported outcome measures, in contrast, were not different across the 2 cohorts.Conclusions.Although L5-S1 TLIF yielded good radiographic correction, it was associated with higher rates of subsequent spine surgery for pseudoarthrosis compared with L4-L5 TLIF. These findings may be related to differences in native segmental alignment and biomechanics across the L4-L5 and L5-S1 motion segments and are important to consider during surgical planning.Level of Evidence.Level IV.