Background: Symptom management in glioma patients remains challenging, as patients suffer from various concurrently occurring symptoms. This study aimed to identify symptom clusters and examine the association between these symptom clusters and patients' functioning. Methods: Data of the CODAGLIO project was used, including individual patient data from previously published international randomized controlled trials (RCTs) in glioma patients. Symptom prevalence and level of functioning were assessed with European Organisation for Research and Treatment of Cancer (EORTC) quality of life QLQ-C30 and QLQ-BN20 self-report questionnaires. Associations between symptoms were examined with Spearman correlation coefficients and partial correlation networks. Hierarchical cluster analyses were performed to identify symptom clusters. Multivariable regression analyses were performed to determine independent associations between the symptom clusters and functioning, adjusted for possible confounders. Results: Included in the analysis were 4307 newly diagnosed glioma patients from 11 RCTs who completed the EORTC questionnaires before randomization. Many patients (44%) suffered from 5-10 symptoms simultaneously. Four symptom clusters were identified: a motor cluster, a fatigue cluster, a pain cluster, and a gastrointestinal/seizures/bladder control cluster. Having symptoms in the motor cluster was associated with decreased (≥10 points difference) physical, role, and social functioning (betas ranged from-11.3 to-15.9, all P < 0.001), independent of other factors. Similarly, having symptoms in the fatigue cluster was found to negatively influence role functioning (beta of-12.3, P < 0.001), independent of other factors. Conclusions: Two symptom clusters, the fatigue and motor cluster, were frequently affected in glioma patients and were found to independently have a negative association with certain aspects of patients' functioning as measured with a self-report questionnaire.