Surgery had been shown to be effective for superimposed peripheral nerve entrapment syndrome in patients with diabetic peripheral neuropathy (DPN), with pain relief and sensation restored. Few studies, however, have reported the quality-of-life outcomes of surgery for the treatment of painful DPN (PDPN). The objective of the present study was to evaluate the effects of microsurgical decompression of multiple entrapped peripheral nerves on pain and health-related quality of life in patients with refractory PDPN of the lower limbs. Eleven patients with intractable PDPN of the lower limbs were recruited for the present study. All the patients underwent microsurgical decompression of the common peroneal nerve, deep peroneal nerve, and posterior tibial nerve. The pain intensity was assessed using the visual analog scale and health-related quality of life was measured using the short-form 36-item quality-of-life survey. Six (54.6%) patients experienced >50% pain relief (both daytime pain and nocturnal pain) at 2 weeks after the decompression procedure and 8 (72.7%) patients at 24 months postoperatively. Two (18.2%) patients experienced a >50% decrease in peak pain at the 2 weeks after the procedure and 8 (72.7%) patients at 24 months. Additionally, the scores from the short-form 36-item quality-of-life survey were significantly improved in the following 2 domains: bodily pain and general health at 2 weeks after the decompression procedure. Also, at 24 months postoperatively, 6 domains had significantly improved, including physical function, bodily pain, general health, social function, role emotional, and mental health. No significant side effects were recorded during the study. Microsurgical decompression of peripheral nerves is an effective and safe therapy for intractable PDPN with superimposed nerve compression. (C) 2016 by the American College of Foot and Ankle Surgeons. All rights reserved.