OBJECTIVE: To determine whether repetitive and cumulative exposure to low-frequency pulsed electromagnetic fields (PEMF) targeting painful feet can reduce neuropathic pain (NP), influence sleep in symptomatic diabetic peripheral neuropathy (DPN), and influence nerve regeneration. DESIGN: Randomized, double-blind, placebo-controlled parallel study. SETTING: Sixteen academic and clinical sites in 13 states. PARTICIPANTS: Subjects (N=225) with DPN stage II or III were randomly assigned to use identical devices generating PEMF or sham (placebo) 2 h/d to feet for 3 months. INTERVENTIONS: Nerve conduction testing was performed serially. MAIN OUTCOME MEASURES: Pain reduction scores using a visual analog scale (VAS), the Neuropathy Pain Scale (NPS), and the Patient's Global Impression of Change (PGIC). A subset of subjects underwent serial 3-mm punch skin biopsies from 3 standard lower limb sites for epidermal nerve fiber density (ENFD) quantification. RESULTS: Subjects (N=225) were randomized with a dropout rate of 13.8%. There was a trend toward reductions in DPN symptoms on the PGIC, favoring the PEMF group (44% vs 31%; P=.04). There were no significant differences between PEMF and sham groups in the NP intensity on NPS or VAS. Twenty-seven subjects completed serial biopsies. Twenty-nine percent of PEMF subjects had an increase in distal leg ENFD of at least 0.5 SDs, while none did in the sham group (P=.04). Increases in distal thigh ENFD were significantly correlated with decreases in pain scores. CONCLUSIONS: PEMF at this dosimetry was noneffective in reducing NP. However neurobiological effects on ENFD, PGIC and reduced itching scores suggest future studies are indicated with higher dosimetry (3000-5000 G), longer duration of exposure, and larger biopsy cohort.