OBJECTIVE: To compare perioperative outcomes, patient-reported outcome measures (PROMs), and minimum clinically important difference achievement after single-level transforaminal lumbar interbody fusion (TLIF) in patients stratified by preoperative comorbidity burden. METHODS: PROMs were administered preoperatively/postoperatively and included Patient-Reported Outcomes Measurement Information System-Physical Function (PROMIS-PF), visual analog scale (VAS), Oswestry Disability Index (ODI), and 12-Item Short-Form Physical Composite Score (SF-12 PCS). Patients were grouped according to preoperative Charlson Comorbidity Index (CCI) <5 (mild to moderate comorbidity) or preoperative CCI >= 5 (severe preoperative comorbidity). A 3:1 propensity score match for age, gender, insurance status, smoking status, and preoperative spinal disease was used to control for significant demographic differences between cohorts. RESULTS: After propensity score matching, 255 patients were included (135 in the CCI <5 cohort; 120 in the CCI >= 5 cohort). The CCI >= 5 cohort showed significantly reduced postoperative VAS back pain score on the day of surgery (P < 0.001, all). Mean PROM differences were noted for postoperative PROMs: VAS back and ODI 6 months, both instances favoring the CCI >= 5 cohort (P < 0.038). The CCI <5 cohort improved from baseline to 1 year for all postoperative PROMs except SF-12 PCS 6 weeks and 12 weeks and SF-12 Mental Composite Score 6 weeks (P < 0.034, all). The CCI >= 5 cohort reported significant improvement from preoperative baseline to 1 year for all postoperative PROMs except ODI 6 weeks, SF-12 Mental Composite Score 6 weeks and 1 year, SF-12 PCS 6 weeks, and PROMIS-PF 6 weeks (P < 0.017, all). Both cohorts reported >50% overall minimum clinically important difference achievement rate for VAS leg, VAS back, ODI, SF-12 PCS, and PROMIS-PF. CONCLUSIONS: The results suggest that patients undergoing MIS TLIF with severe comorbidities can expect a similar postoperative trajectory for disability, leg and back pain, and physical function. However, long-term (1 year) mental health improvement from preoperative baseline was noted only in the mild to moderate comorbidity group.