Hypermobile Ehlers Danlos Syndrome (hEDS)/hypermobility spectrum disorders (HSD) are incapacitating and painful syndromes involving a generalized connective tissue disorder with joint hypermobility and musculoskeletal complications. A neuropathic component is clinically likely given frequent burning sensations, hypoesthesia, or allodynia. Small fiber neuropathy (SFN) refers to the dysfunction or damage of A-I and C-fibers, which relay thermal and nociceptive information as well as mediating autonomic function. SFN has been suggested by prior studies in hEDS but these early findings (case series Na20) with sole reliance on intraepidermal nerve fiber density (IENFD) called for a larger sample combined with functional testing. In this retrospective chart extraction from 79 hEDS/HSD patients referred to a pain center due to neuropathic pain or dysautonomia, both functional (Quantitative Sensory Testing (QST), N=79) and structural (IENFD, N=69) evaluations of small nerve fibers were analyzed in combination with clinical data.A small fiber neuropathy was definite (both abnormal IENFD and QST) in 40/69 patients (58%), possible (one abnormal test) in 23/69 patients (33%) and excluded (both normal) in only 6/69 patients (9%). These results add strong evidence for a peripheral neuropathic contribution to pain symptoms in hEDS/HSD, in addition to the known nociceptive and central sensitization components. Such neuropathic contribution could raise the hypothesis of a neurological cause of hEDS, the only EDS syndrome still without a known genetic cause. Hence, our data is leading the way to a better stratification of this very heterogeneous population, which could improve symptom management and expand pathophysiological research. This article is protected by copyright. All rights reserved.