Aims: The aim of this study was to assess whether surgical decompression of nerves in the lower extremity in people with painful diabetic polyneuropathy would have an effect on health-related quality of life and to determine minimal clinically important differences in pain and quality of life scores. Methods: The design was a randomized controlled trial in which 42 participants with painful diabetic painful neuroapthy underwent unilateral decompression of nerves in their left or right leg, using the other leg as a control, with 12 months follow-up. Surgical decompression was performed at the tibial, superficial, deep and common peroneal nerves. Preoperatively, and at 6 and 12 months post operatively, a visual analogue scale for pain and the 36 item short-form health survey and EuroQual 5 Dimensions questionnaires were completed. Results: At 12 months follow-up, the visual analogue scale was significantly reduced, but decompression surgery did not significantly alter health-related quality of life scores. The minimal clinically important difference for visual analogue scale reduction was determined at 2.9 points decrease, a threshold reached by 42.5% of the study population. Conclusions: Although decompression surgery does not influence health-related quality of life, it achieves a clinically relevant reduction of pain in ~42.5% of people with diabetic peripheral neuropathy. It can therefore be considered for patients who do not adequately respond to pain medication.