Purpose To explore feasibility, tolerability, dosimetry and probable efficacy of intravenous endoradiotherapy with carrier-added 4-[$^{131}I$]iodo-L-phenylalanine (c.a. $^{131}I$-IPA) in refractory high-grade glioma. Methods Two male patients (45 and 50 years), with longstanding, extensively pre-treated gliomas and evidence of progression underwent single intravenous injections of 2 and 4 GBq of c.a. $^{131}I$-IPA, respectively. Tumour targeting was verified by $^{131}I$-IPA single-photon emission computed tomography (SPECT). Metabolic and morphological changes indicative of tumour response were assessed by sequential [$^{18}F$] fluoroethyltyrosine ($^{18}F$-FET) positron emission tomography (PET) and contrast-enhanced magnetic resonance imaging (MRI) following therapy. Further monitoring included clinical state, safety laboratory, quality of life and dosimetry. Absorbed mean organ and whole-body doses were determined according to the Medical Internal Radiation Dose (MIRD) scheme using OLINDAEXM based on serial planar scintigraphy. Results Both patients tolerated the treatment well. No evidence of acute or delayed organ toxicity was observed. $^{131}I$-IPA accumulated in the tumour recurrences identified by MRI/$^{18}F$-FET. In patient 1, PET showed progressively decreasing maximum standardised uptake values ($SUV_{max}$) over 10 months, indicating metabolic response, paralleled by reduced contrast enhancement and tumour volume on MRI. Progression occurred 18 months after therapy. Treatment was repeated using 6.6 GBq of $^{131}I$-IPA, to which no response was observed. Patient 2, followed-up for 3 months after therapy, showed stable disease on MRI and PET. Mean absorbed whole body doses ranged from 0.13 to 0.17 mSv/MBq, with the highest absorbed organ doses to kidneys, bladder and heart (0.86-1.23; 0.49-0.6 and 0.45-0.56 mSv/MBq). Conclusion Systemic endoradiotherapy using up to 6.6 GBq of c.a.$^{131}I$-IPA is not associated with clinically detectable toxicity. Measurable anti-tumour effects in gliomas were observed. $^{131}I$-IPA warrants further evaluation as glioma therapy.