BACKGROUND: Various treatment modalities are available for local antibiotic therapy in spondylodiscitis (SD) and isolated spinal epidural empyema (ISEE), but there is no evidence-based recommendation. Postoperative epidural suction-irrigation drainage (ESID) is thought to reduce bacterial load, which may prevent the development of relapse, wound healing, hematogenous spread, and systemic complications. We evaluated the efficacy of postoperative ESID over 20 years on disease progression and outcome in SD and ISEE. METHODS: Detailed demographic, clinical, imaging, laboratory, and microbiological characteristics were examined in our cohorts of 208 SD and ISEE patients treated with and without ESID at a university spine center in Germany between 2002 and 2022. Between-group comparisons were performed to identify meaningful differences for the procedure. RESULTS: We included data from 208 patients (142 SD, 68.3% vs. 66 ISEE, 31.7%) of whom 146 were ESID patients (87 SD, 59.6% vs. 59 ISEE, 40.4%) and 62 were NON-ESID patients (55 SD, 88.7% vs. 7 ISEE, 11.3%). ESID patients with SD showed more frequent SSI (ESID: 22, 25.3% vs. NON-ESID: 3, 5.5%, p = 0.003), reoperations due to empyema persistence or instability (ESID: 37, 42.5% vs. NON-ESID: 12, 21.8%, p = 0.012), and a higher relapse rate (ESID: 21, 37.5% vs. NON-ESID: 6, 16.7%, p = 0.037) than NON-ESID patients with SD. The success rate in NON-ESID patients with SD was higher than in ESID patients with SD (ESID: 26, 29.9% vs. NON-ESID: 36, 65.6%, p < 0.001). Multivariate binary logistic regression analysis showed that ESID therapy (p < 0.001; OR: 0.201; 95% CI: 0.089-0.451) was a significant independent risk factor for treatment failure in patients with SD. CONCLUSIONS: Our retrospective cohort study with more than 20 years of experience in ESID technique shows a negative effect in patients with SD in terms of surgical site infections and relapse rate.