Objective: The aim of this study was to evaluate the accuracy of different methods for evaluation of small fiber neuropathy (SFN) using intra epidermal nerve fiber density (IENFD) as the reference standard. Background IENFD is the current standard for evaluation of SFN but limited by invasiveness, expense and availability. Heat-induced neurogenic vasodilation by Laser Doppler Imaging (LDI), cold detection thresholds (CDT) and heat perception (HP) are noninvasive nerve function alternatives whose accuracy relative to morphological IENFD is unknown. Design/Methods: We performed a retrospective chart review of 75 patients suspected of having SFN at the Toronto General Hospital, University Health Network from 2008-2011. A detailed history and clinical examination, laboratory studies, nerve conduction studies (NCS), CDT, HP, LDI and IENFD were performed in all patients. We quantitatively compared the results of clinical evaluation including pain on the visual analogue scale (VAS), LDI, CDT and HP relative to IENFD for the diagnosis of SFN. Results: The mean IENFD was 7.52 +/- 4.12 with a median value of 7.59 and interquartile range of 4.64-10.91 (25% to 75%). 34.7% had abnormal IENFD and 65.3% had normal IENFD according to published criteria (normal defined as > 5.4 fibers/mm). Low-magnitude correlation was observed between IENFD and CDT (R2 =0.0812, p Conclusions: None of the objective measures reflected IENFD with very good diagnostic validity, but of these small fiber non-invasive methods, CDT had the highest level of accuracy, while we could not demonstrate acceptable performance of LDI. Alternate non-invasive methods for the determination of small fiber function or morphology are urgently needed. Disclosure: Dr. Ebadi has nothing to disclose. Dr. Perkins has nothing to disclose. Dr. Katzberg has received personal compensation for activities with Genzyme as a speaker and participant on an advisory board. Dr. Katzberg has received research support from Griffolds Biotherapeutics. Dr. Bril has received personal compensation for activities with Talecris Biotherapeutics as a consultant. Dr. Bril has received research support from Talecris Biotherapeutics.