Abstract BACKGROUND The value of re-resection in recurrent glioblastoma remains controversial as a randomized trial that specifies intentional incomplete resection cannot be justified ethically. Here, we aimed to (I) explore the prognostic role of extent of re-resection using the previously proposed RANO classification (based upon residual contrast-enhancing (CE) and non-CE tumor), and to (II) define factors consolidating the surgical effects on outcome. MATERIAL AND METHODS The RANO resect group retrospectively compiled a global, eight-center cohort of patients with first recurrence from previously resected glioblastomas. The combined associations of re-resection and other clinical factors with outcome were analyzed. Kaplan-Meier survival analysis and log-rank test were applied to calculate survival, and Cox’s proportional hazard regression models to adjust for multiple variables (significance level: p ≤ 0.05). Propensity score-matched analyses were constructed to mimic randomized clinical trials comparing the different RANO classes. RESULTS We studied 681 with first recurrence of IDH-wildtype glioblastomas, including 310 patients who underwent re-resection. Re-resection was associated with prolonged survival even when stratifying for clinical and molecular confounders on multivariate analysis (HR for re-resection: 0.65, CI: 0.5-0.8; p = 0.001); and ≤1 cm3 residual CE tumor was associated with longer survival than non-surgical management. Accordingly, ‘maximal CE resection’ (class 2) had superior survival compared to ‘submaximal CE resection’ (class 3) (median OS after recurrence: 12 vs. 9 months; p = 0.003). Administration of (radio-)chemotherapy further augmented the survival associations of smaller residual CE tumor. The prognostic role of residual CE tumor was confirmed in propensity score analyses. Conversely, ‘supramaximal CE resection’ targeting also non-CE tumor (class 1) was not associated with prolonged survival but frequently accompanied by post-operative deficits, hampering further adjuvant treatment. CONCLUSION The RANO resect classification serves to stratify patients with re-resection of glioblastoma. Complete CE resection according to RANO resect class 1 and 2 is prognostic of outcome. The beneficial effects of re-resection might be consolidated by (radio-)chemotherapy, and avoidance of post-operative deficits hampering such treatment is of critical importance.