For a study, researchers sought to find a link between cachexia and prognosis in patients with advanced-stage small-cell lung cancer (ES-SCLC) who had received first-line immunotherapy. Some systematic inflammatory and nutritional markers were also assessed for their predictive significance. From June 2019 to February 2021, data from 123 ES-SCLC patients who received immunotherapy as first-line treatment in a single facility were evaluated. Patients with more than 5% weight loss in the previous 6 months or more than 2% weight loss with a BMI less than 20 kg/m2 were considered to have developed cachexia after immunotherapy. Response rate, progression-free survival (PFS), and overall survival were all used as endpoints (OS). To find the parameters linked to PFS and OS. According to the results, cachexia was detected in 51 patients (41.5%) after six months of beginning treatment. Patients with cachexia had a lower treatment response and survival rate than those without. The median overall survival time (OST) was 14.4 months (95% CI: 13.3–15.6). All patients’ median progression-free survival (PFS) was 8.1 months (95% CI: 7.0–9.2). Patients without bone metastases at diagnosis (HR=2.362,95% CI:1.452-3.842; P=0.001), without cachexia (HR = 1.802,95% CI: 1.121-2.895; P=0.015), and with lower total protein change (HR=1.799,95% CI: 1.084–2.984; P=0.023) had significantly longer median PFS. Patients had a poor ECOG PS (HR=1.904, 95% CI: 1.017–3.564; P=0.044), greater baseline SII (HR=2.135, 95% CI: 1.117–4.080; P=0.022), cachexia (HR=2.020,95% CI: 1.075–3.795; P=0.029), advanced M stage (HR=3.111,95% CI: 1.545–6.262; P=0.001) and higher post-treatment SIRI (HR=2.135,95% CI: 1.281–4.697; P=0.007). After first-line immunotherapy, patients with ES-SCLC who developed cachexia had a poor prognosis. The outcomes further showed that baseline SII and SIRI at six weeks following treatment appeared to be potential predictors of OS in patients with ES-SCLC receiving first-line immunotherapy.