Abstract Background At the group level, health-related quality of life (HRQoL) in patients with IDH-mutant diffuse glioma grades 2 and 3 seems to remain stable over time. However, clinical experience indicates that there are patients with unfavorable outcomes on key HRQoL subdomains. The aim of this longitudinal population-based study, following patients over a period of 12 months from surgery, was to describe individual-level data on global health status and fatigue score and explore possible predictors of deterioration. Methods All patients undergoing surgery for presumed glioma grades 2 or 3 at the Sahlgrenska University Hospital during 2017–2022, were screened for the study. Patients were invited to complete the European Organization of Research and Treatment of Cancer core questionnaires and brain module at baseline, 3 and 12 months postoperatively. Data is reported with respect to minimal clinical important difference (MCID). Results We included 51 patients with IDH-mutant diffuse glioma grades 2 or 3. There was no difference in group-level data of either global health status or fatigue score from baseline to the 12-month follow-up (P-value > .05). Unfavorable individual changes (beyond MCID) in global health status and fatigue score were observed in 12 and in 17 patients, respectively (23.5% and 33.3%). A lower proportion of proton radiotherapy was found in patients with unfavorable changes in fatigue (10/15, 66.7%) compared to all other patients undergoing radiotherapy (22/23, 95.7%, P-value .03). Conclusions Deterioration beyond MCID was seen in approximately one-third of patients. Changes in global health status could not be predicted, but changes in fatigue may be influenced by tumor-targeted and symptomatic treatment.