: We aimed to evaluate the prognostic value of imaging biomarkers on 18F-FDG PET/CT in extensive-stage small-cell lung cancer (ES-SCLC) patients undergoing first-line chemo-immunotherapy. In this multicenter and retrospective study, we considered two cohorts, depending on the type of first-line therapy: chemo-immunotherapy (CIT) versus chemotherapy alone (CT). All patients underwent baseline 18-FDG PET/CT before therapy between June 2016 and September 2021. We evaluated clinical, biological, and PET parameters, and used cutoffs from previously published studies or predictiveness curves to assess the association with progression-free survival (PFS) or overall survival (OS) with Cox prediction models. Sixty-eight patients were included (CIT: CT) (36: 32 patients). The median PFS was 5.9:6.5 months, while the median OS was 12.1:9.8 months. dNLR (the derived neutrophils/(leucocytes-neutrophils) ratio) was an independent predictor of short PFS and OS in the two cohorts ( < 0.05). High total metabolic tumor volume (TMTV if > 241 cm) correlated with outcomes, but only in the CIT cohort (PFS for TMTV in multivariable analysis: HR 2.5; 95%CI 1.1-5.9). Baseline 18F-FDG PET/CT using TMTV could help to predict worse outcomes for ES-SCLC patients undergoing first-line CIT. This suggests that baseline TMTV may be used to identify patients that are unlikely to benefit from CIT.