The impact of rituximab on health-related quality of life (HRQoL) in primary central nervous system lymphoma patients is not well-known. We determined the impact of rituximab added to standard high-dose methotrexate-based treatment on HRQoL from patients in a large randomised trial.Patients from a large phase III trial (HOVON 105/ALLG NHL 24), randomised to standard chemotherapy with or without rituximab and followed by 30Gy whole brain radiotherapy (WBRT) in patients ≤60 years, completed the EORTC QLQ-C30 and QLQ-BN20 questionnaires before and during treatment, and up to 24 months of follow-up or progression. Differences between treatment arms over time in global health status, role functioning, social functioning, fatigue, and motor dysfunction were assessed. Differences ≥10 points were deemed clinically relevant. The effect of WBRT on HRQoL was analysed in irradiated patients.160/175 patients eligible for the HRQoL study completed at least one questionnaire and were included. Over time, scores improved statistically significant and clinically relevant in both arms. Between arms, there were no differences on any scale (range: -3.8 to +4.0). Scores on all scales were improved to a clinically relevant extent at 12 and 24 months compared to baseline in both arms, except for fatigue and motor dysfunction at 12 months (-7.4 and -8.8, respectively). In irradiated patients (N=59), scores in all preselected scales except motor dysfunction, remained stable up to 24 months compared to shortly after WBRT, overall mean difference ranging between 0.02 and 4.570.Compared to baseline, treatment resulted in improved HRQoL scores. The addition of rituximab to standard chemotherapy did not impact HRQoL over time. WBRT did not result in deterioration of HRQoL in the first two years.