Background: Computed tomography (CT)-derived body composition parameters, including skeletal muscle and fat indices, are prognosticators in oncology. Most studies focus on baseline body-composition parameters; however, changes during treatment may provide better prognostic value. Standardized methods for measuring/reporting these parameters remain limited. Methods: This retrospective study included patients who were treated with immunotherapy for non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), or melanoma between 2017 and 2024 and had technically adequate baseline and follow-up CT scans. Body composition was analyzed using a novel, fully automated software (CompoCT) for L3 slice selection and segmentation. Body composition indices (e.g., skeletal muscle index [SMI]) were calculated by dividing the cross-sectional area by the patient’s height squared. Results: The cohort included 376 patients (mean [SD] age 66.4 [11.4] years, 67.3% male, 72.6% NSCLC, 14.6% RCC, and 12.8% melanoma). During a median follow-up of 21 months, 220 (58.5%) died. Baseline body composition parameters were not associated with mortality, except for a weak protective effect of higher SMI (HR = 0.98, p = 0.043). In contrast, longitudinal decreases were strongly associated with increased mortality. Relative decreases in SMI (HR, 1.17; 95% CI, 1.07–1.27) or subcutaneous fat index (SFI) (HR, 1.11; 95% CI, 1.07–1.15) significantly increased mortality risk. Multivariate models showed similar concordance (0.65) and identified older age, NSCLC tumor type, and relative decreases in SMI and SFI (per 5% units) as independent predictors of mortality. Conclusions: Longitudinal decreases in skeletal muscle and subcutaneous fat were independent predictors of mortality in immunotherapy-treated patients. Automated CT-based body composition analysis may support treatment decisions during immunotherapy.