INTRODUCTION: Intranasal esketamine (ESK) is a novel therapy option in patients with treatment-resistant depression (TRD). Patients with a history of electroconvulsive therapy (ECT) non-response (ECT+) in the current episode have usually been excluded from previous studies. Data on the effectiveness of ESK in ECT non-responders are sparse. METHODS: In this retrospective study, we investigated the effectiveness of intranasal ESK in real-world inpatients with (ECT+, n = 39) history of ECT non-response compared to patients who have not received an adequate course of ECT in their current episode (ECT-, n = 57). A factorial analysis of variance (ANOVA) has been used to determine the impact of ECT non-response on treatment outcome. RESULTS: A total of n = 96 patients (mean age 47.0; 52.1% women) with TRD were included in this study. There was a significant main effect of history of ECT non-response on MADRS score in the ANOVA (F = 10.386, p = 0.002). However, there was no significant interaction effect of time (pre-treatment, post-treatment)*history of ECT non-response in current episode (F = 2.166, p = 0.143). The response (34.9% vs. 21.9%, χ2 = 1.498, p = 0.167) and remission rates (24.4% vs. 12.1%, χ2 = 1.861, p = 0.141) were none significantly lower in the ECT + group than in the ECT- group. There was significant improvement in MADRS and BDI-II in the ECT + group. No major safety concerns occurred during the study. CONCLUSION: There was no significant impact of ECT non-response on esketamine treatment outcome. Our results support the approach to offer esketamine to ECT non-responders given that the array of treatment alternatives is limited for these patients.