Background: For patients with extensive-disease small cell lung cancer (ED-SCLC), amrubicin monotherapy is an important therapy in the treatment of recurrence, but there has been no adequate evaluation of how effective it actually is after failure of first-line chemotherapy including immune checkpoint inhibitor (ICI). Therefore, the purposes of this study are to determine the proportion of patients who received amrubicin monotherapy in the treatment of relapse after first-line treatment with ICI (arm A) and to investigate the efficacy of amrubicin therapy after arm A compared with after chemotherapy without ICI (arm B). Methods: Consecutive 40 pts with ED-SCLC NSCLC were retrospectively assessed who underwent ICI-containing chemotherapy (n = 19) or standard cytotoxic chemotherapy (n = 21) in the 1st-line setting between 2017 and 2020. Results: In arm A, 3 of 19 patients (16%) were still on first-line ICI maintenance therapy, 2 (2/19; 11%) had ICI treatment adverse events (interstitial pneumonia, cardiopulmonary arrest), and 1 patient could not receive second-line therapy due to a decrease in performance status (PS) to 3. In arm B, 11 of 21 patients (52%) did not receive amrubicin as second-line therapy, including 1 patient with worsening PS, 1 patient with adverse events (hematologic toxicity), 1 patient refusal, and 6 patients with combination of ICI and chemotherapy. 23 patients (arm A; 13 (57%), arm B; 10 (43%)) were able to receive amrubicin monotherapy, including 7 patients (6 cases vs 1 case) were sensitive relapses, and 16 (7 vs 9 cases) were refractory relapses. There was no significant difference in either PFS or survival after first-line treatment in 16 patients with refractory relapse who received amrubicin as second-line treatment (PFS: 4.8 vs 5.2 months, p = 0.51), (median survival after first-line treatment: 9.6 vs 12.8, p = 0.75). Conclusions: Patients who received ICI in the first-line treatment were fully eligible to receive amrubicin in the second-line treatment. The recurrence pattern tended to be sensitive relapse and we found that the efficacy of amrubicin in refractory relapse was not affected by the administration of ICI in the first-line treatment.