Purpose <p>Seizures are common in glioblastoma (GBM) and substantially affect patient quality of life. Because the thalamus is a key hub in cortico–thalamo–cortical circuits and is a therapeutic target for neuromodulation in drug-resistant epilepsy, we hypothesized that thalamic tumor involvement may be associated with reduced seizure expression in GBM.</p> Methods <p>We retrospectively reviewed consecutive patients who underwent initial craniotomy for suspected supratentorial glioma between January 2009 and March 2024 and were diagnosed with GBM, IDH-wildtype (CNS WHO Grade 4). Patients whose lesions were confined to the thalamus without cerebral hemispheric involvement during the disease course were excluded. Thalamic involvement at diagnosis was defined on baseline gadolinium-enhanced T1-weighted MRI. Two endpoints were analyzed separately: seizures at diagnosis (preoperative) and seizures during postoperative follow-up (postoperative day 8 onward). Associations were evaluated using Fisher’s exact test.</p> Results <p>Among 113 eligible patients, 16 had thalamic involvement at diagnosis. No seizures were observed at diagnosis in patients with thalamic involvement (0/16) compared with 26/97 (27%) without thalamic involvement (<i>p</i> = 0.0208). Similarly, no postoperative seizures occurred in the thalamic-involvement group (0/16) compared with 39/97 (40%) without thalamic involvement (<i>p</i> = 0.00106). Among patients without thalamic involvement at diagnosis (<i>n</i> = 97), subsequent thalamic invasion was not significantly associated with postoperative seizures (5/24 [21%] vs. 25/73 [34%], <i>p</i> = 0.31).</p> Conclusion <p>Thalamic involvement at diagnosis was associated with an absence of seizures at presentation and during postoperative follow-up in supratentorial GBM. These findings suggest a distinct seizure phenotype in GBM with thalamic involvement and warrant validation in larger cohorts.</p>