Objective To compare the efficacy differences of immune checkpoint inhibitors (ICIs) in first-line versus subsequent-line immunotherapy for extensive-stage small-cell lung cancer (ES-SCLC). Methods Data on patients diagnosed with small cell lung cancer (SCLC) between January 2021 and December 2023 were retrospectively collected from West China Hospital of Sichuan University. According to the time at which ICIs were used, patients were divided into first-line immunotherapy group and subsequent-line immunotherapy group. Multivariate Cox proportional hazards regression model analysis was used to analyze the influencing factors of overall survival (OS). Results A total of 166 patients were included. Among them, there were 121 cases in the first-line immunotherapy group and 45 cases in the subsequent-line immunotherapy group. The median follow-up lasted for 24.07 (16.27, 31.70) months. Fifty-three patients died in the first-line immunotherapy group and 28 in the subsequent-line immunotherapy group. The median OS of the two groups was 28.6 and 16.2 months, respectively, and the difference was statistically significant (log-rank P=0.021). There was also a significant difference in time to disease progression free survival between the two groups (9.67 and 7.90 months, respectively; log-rank P=0.008). There was no difference in OS between patients who continued and those who did not continue an ICI-containing regimen after disease progression on first-line immunotherapy (median OS of 37.1 and 24.8 months for continuation of immunotherapy versus no immunotherapy, respectively; log-rank P=0.600). Multivariate Cox regression analysis found that body mass index≥24 kg/m2 (P=0.014) and undergoing prophylactic cranial irradiation (P=0.036) reduced the risk of death. Conclusions ES-SCLC patients with first-line initial therapy using ICIs-containing drugs had better OS than those with ICIs in the subsequent-line, and re-selection of the same or different ICIs after progression of those who had used ICIs drugs in the first line did not improve survival.