Abstract Purpose: To investigate the prognostic relevance of temporal muscle thickness (TMT) as a surrogate parameter of skeletal muscle status in patients with newly diagnosed glioblastoma. Experimental Design: We assessed TMT in cranial MRI of 755 patients enrolled in the CENTRIC EORTC 26071–22072 study (n = 508) and CORE study (n = 247). We used predefined sex-specific TMT cut-off values to categorize “patients at risk of sarcopenia” and “patients with normal muscle status” at baseline. Furthermore, we categorized patients according to the extent of TMT loss over time. Associations with progression-free survival (PFS) and overall survival (OS) were evaluated using the Cox model adjusted for other exploratory variables. Results: Patients at risk of sarcopenia (CENTRIC; n = 158/508, 31.1%; CORE; n = 87/247, 35.2%) at baseline had significantly higher risk of progression and death than patients with normal muscle status in both study cohorts [CENTRIC: PFS = HR 0.16; 95% confidence interval (CI), 0.12–0.21; P < 0.001; OS = HR 0.341; 95% CI, 0.27–0.44; P < 0.001; CORE: PFS = HR 0.29; 95% CI, 0.21–0.39; P < 0.001; OS = HR, 0.365; 95% CI, 0.27–0.49; P < 0.001]. Similar results were obtained in multivariate Cox models adjusted for other important prognostic parameters. The extent of TMT loss over time showed a significant inverse correlation with median OS times in patients at risk for sarcopenia (CENTRIC: P < 0.001; CORE: P = 0.005), but not in patients with normal baseline muscle mass (CENTRIC: P = 0.538; CORE: P = 0.28). Conclusions: TMT identifies ambulatory patients with newly diagnosed glioblastoma at risk for progressive sarcopenia and adverse outcomes. Early intervention may prevent skeletal muscle loss and improve patient outcome.