OBJECTIVE Impaired rate-dependent depression of the Hoffman reflex (HRDD) is a marker of spinal inhibitory dysfunction and has previously been associated with painful neuropathy in a proof-of-concept study in patients with type 1 diabetes. We have now undertaken an assessment of HRDD in patients with type 1 or type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 148 participants, including 34 healthy control subjects, 42 patients with painful diabetic neuropathy, and 62 patients with diabetic neuropathy without pain, underwent an assessment of HRDD and a detailed assessment of peripheral neuropathy, including nerve conduction studies, corneal confocal microscopy, and thermal threshold testing. RESULTS Compared with healthy control subjects (P < 0.001) and patients without pain (P < 0.001), we found that HRDD is impaired in patients with type 1 or type 2 diabetes with neuropathic pain. These impairments are unrelated to diabetes type and the presence or severity of neuropathy. In contrast, patients without neuropathic pain (P < 0.05) exhibited enhanced HRDD compared with control subjects. CONCLUSIONS We suggest that loss or impairment of HRDD may help to identify a subpopulation of patients with painful diabetic neuropathy mediated by impaired spinal inhibitory systems who may respond optimally to therapies that target spinal or supraspinal mechanisms. Enhanced RDD in patients without pain may reflect engagement of spinal pain–suppressing mechanisms.