The effective range of negative pressure wound therapy (NPWT) lies between 50 mmHg and 150 mmHg, yet no optimal pressure has been identified. This study assessed the effect of negative pressure level on the rate and duration of wound healing in patients with non-ischaemic diabetic foot ulcers (DFUs). Patients were randomised to standard (–120 mmHg; n=87) or high (–160 mmHg; n=88) NPWT, managed following a standard wound care protocol and followed until complete healing or for a maximum of 12 months. The high NPWT group had a significantly greater rate of complete wound healing (P<0.00001), significantly shorter time to healing (P=0.003), significantly lower amputation rate (P=0.003) and fewer deaths (P=0.07) than the standard NPWT group. Greater negative pressure accelerated healing and reduced major amputations and death in patients with non-ischaemic DFUs.