We present three patients off-label treated with intravenous (IV) esketamine for treatment-resistant depression (TRD) of whom two (patients A and B, aged 72 and 77 years, respectively) were admitted to the psychiatric unit with depressive symptoms and one outpatient (patient C, aged 66 years). After six esketamine treatments over a period of three weeks, two patients showed improvement, as measured with the Hamilton Rating Scale for Depression (HRSD): the HRSD-score of patient A decreased from 36 to 9 and of patient C from 18 to 10. Patient B had no response to esketamine but was treated successfully with electroconvulsive therapy (ECT). Despite the presence of various somatic comorbidities, esketamine treatment appeared safe and well-tolerated by the patients. After the index treatment, patients A and C received maintenance treatment with esketamine (once every 4-6 weeks). We recommend to consider off-label IV esketamine treatment in patients suffering TRD with or without suicidality.