BACKGROUND AND OBJECTIVE: Progressive multifocal leukoencephalopathy (PML) is a severe, disabling infection caused by JC virus reactivation. PML-related disability complicates the MRI monitoring needed to assess treatment interventions in clinical trial or compassionate use settings. Portable ultra-low-field MRI (pULF-MRI) offers a convenient approach when such frequent imaging is needed. We evaluated the potential utility of pULF-MRI as an adjunctive tool for decreasing the burden of clinical study participation and clinical management in PML. METHODS: We examined paired high-field (HF) and pULF-MRI scans from 11 patients, aged 49 ± 15 years. pULF-MRI images with corresponding HF-MRI were coupled to depict key imaging findings of PML, including three patients with longitudinal evaluations, one with bedside pULF-MRI. The images were then independently assessed by two blinded raters, not involved in image acquisition or initial evaluations, who sequentially rated diagnostic accuracy of pULF-MRI scans compared to the HF-MRI. Longitudinal evaluations were performed for three patients, one with bedside pULF-MRI. RESULTS: T2-FLAIR lesions were detected with pULF-ULF in all cases when present on HF-MRI. Median sensitivity and specificity were 62% and 100%, respectively. T1WI hypointense areas showed similar performance. Focal volume loss was present in 8/11 HF-MRI scans, with sensitivity and specificity of detection by pULF-MRI of 100% and 94%, respectively. Contrast enhancement was seen in a single case on both pULF- and HF-MRI. Follow-up pULF-MRI showed lesion changes in two cases, and stable findings in one case, consistent with HF-MRI. DISCUSSION: pULF-MRI shows promise in evaluation and monitoring of PML, showing moderate-to-high accuracy even when evaluations were unaided by HF-MRI. Our results highlight a potential application of pULF-MRI for facilitating participation in PML clinical research and more generally as a way to reduce burden of clinical management for this disabled patient population.