ABSTRACT: Endogenous pain modulation, as tested by the conditioned pain modulation (CPM) protocol, is typically less efficient in chronic pain patients compared to healthy controls. We aimed to assess whether CPM is less efficient in painful compared to non-painful diabetic polyneuropathy (DPN) patients. Characterization of the differences in central pain processing between these two groups might provide a central nervous system explanation to the presence or absence of pain in diabetic neuropathy in addition to the peripheral one.271 patients with DPN underwent CPM testing and clinical assessment, including quantitative sensory testing. Two modalities of the test stimuli (heat and pressure) conditioned to cold noxious water were assessed and compared between painful and non-painful DPN patients. No significant difference was found between the groups for pressure pain CPM, however painful DPN patients demonstrated unexpectedly more efficient CPMHEAT ( -7.4±1.0 vs. -2.3±1.6; p=0.008). Efficient CPMHEAT was associated with higher clinical pain experienced in the 24 hours prior to testing (r=-0.15; P=0.029) and greater loss of mechanical sensation (r=-0.135; P=0.042). Moreover, patients who had mechanical hypoesthesia demonstrated more efficient CPMHEAT (p=0.005). More efficient CPM among painful patients might result from central changes in pain modulation, but also from altered sensory messages coming from tested affected body sites. This calls for the use of intact sites for proper assessment of pain modulation in neuropathy patients.