Purpose <p>The adverse prognostic impact of cancer cachexia is well recognized. We aimed to evaluate the prognostic impact of weight loss during first-line platinum-based chemo(immuno)therapy in patients with extensive-disease small-cell lung cancer (ED-SCLC).</p> Methods <p>We retrospectively reviewed 187 of 346 ED-SCLC patients (54%) treated between 2009 and 2021, and collected body weight at three time points: 6&#xa0;months before, at the start of the first cycle, and at the beginning of the third cycle of initial chemotherapy. Based on pretreatment cachexia defined according to the Fearon criteria (weight loss &gt; 5% or &gt; 2% with BMI &lt; 20&#xa0;kg/m² within 6&#xa0;months) and &gt; 2% weight loss from the start of chemotherapy to the beginning of the third cycle, we classified patients into four groups: those without weight loss both before and during chemotherapy (<i>n</i> = 75) (non-weight-loss group), those without weight loss before but with weight loss during chemotherapy (<i>n</i> = 34), those with weight loss before but not during chemotherapy (<i>n</i> = 46), and those with weight loss both before and during chemotherapy (<i>n</i> = 32). We evaluated survival outcomes and gastrointestinal toxicities during the first two cycles.</p> Results <p>Median overall survival (OS) differed significantly among the groups (<i>p</i> = 0.020), with the non-weight-loss group showing more favorable survival than the other groups (adjusted hazard ratios, 1.51–1.65; all <i>p</i> ≤ 0.05). The non-weight-loss group experienced fewer grade ≥ 2 anorexia and nausea/vomiting events during the first two cycles.</p> Conclusions <p>In patients with ED-SCLC, the absence of weight loss before and during chemotherapy was associated with longer OS and fewer gastrointestinal toxicities. These findings underscore the importance of early supportive care to prevent weight loss, including proactive management of gastrointestinal toxicities during chemotherapy.</p>