Abstract Purpose Concomitant chemoradiation followed by repeat (dose-deescalated) irradiation has become standard of care in treating childhood diffuse intrinsic pontine glioma (DIPG) during first line treatment and at first progression. Progression after re-irradiation (re-RT) is in most cases symptomatic and either treated systemically with chemotherapy or new innovative approaches including targeted therapy. Alternatively, the patient receives best supportive care. Data on second re-irradiation in DIPG patients with second progression and good performance status are sparse. This is a case report of second short-term re-irradiation to shed further light on this option. Methods Retrospective case report of a 6-year-old boy with DIPG receiving a second course of re-irradiation (with 21.6 Gy) as part of an individual multimodal approach in a patient with very low symptom burden. Results The second course of re-irradiation was feasible and well tolerated. No acute neurological symptoms or radiation-induced toxicity occurred. Overall survival was 24 months after initial diagnosis. Conclusion A second course of re-irradiation can be an additional tool in patients with progressive disease after first- and second-line irradiation. It is unclear whether and to what extent it contributes to progression-free survival prolongation and if—since our patient was asymptomatic—progression-associated neurological deficits can be alleviated.