OBJECTIVE: The aim of this study was to report 2 unrelated women with demyelinating motor-predominant neuropathy in whom pathogenic variants in the proteolipid protein 1 gene (PLP1) were identified. METHODS: Two unrelated female individuals underwent nerve conduction studies, EMG, evoked potential tests, neuroimaging, and targeted genetic testing. RESULTS: The first patient, a 34-year-old woman, presented with foot drop and had electroneurographic findings consistent with a demyelinating motor-predominant neuropathy, with genetic testing revealing a pathogenic PLP1 variant. The second patient, also middle-aged, had a different pathogenic PLP1 variant and a clinical diagnosis of progressive spastic paraplegia, with detailed electrophysiologic assessment demonstrating a coexistent demyelinating motor-predominant neuropathy. DISCUSSION: These cases demonstrate that PLP1-related disease in women can present in the fourth and fifth decades as a sporadic demyelinating motor-predominant neuropathy, which may be mistaken for an acquired immune-mediated neuropathy. In middle-aged women presenting with an apparently sporadic demyelinating motor neuropathy, genetic testing should, therefore, include PLP1. Recognizing PLP1 disease has important implications, such as access to emerging genetic therapies and the opportunity to offer preimplantation genetic testing to reduce the risk of transmission to offspring.