The formation of heterotopic ossification is a relatively common, yet rarely discussed, cause of re-ulceration after previous partial metatarsal amputation. Excessive bone growth at the amputation site has the potential to create an unwanted prominence on the weightbearing surface of the foot, intuitively increasing plantar pressure and placing the neuropathic patient at greater risk of re-ulceration and limb loss. The aim of the present study was to assess the efficacy of single-dose radiation therapy in preventing recurrent heterotopic ossification. The inclusion criteria consisted of a history of clinically relevant heterotopic ossification formation after partial metatarsal amputation with subsequent partial metatarsal amputation for heterotopic ossification resection, followed by prophylactic single-dose radiation therapy. Eleven consecutive patients meeting the inclusion criteria were identified for the present study. Before the intervention, 10 (91%) patients demonstrated formation of mid- to high-grade heterotopic ossification, and 9 (82%) patients exhibited an associated neuropathic ulceration. On follow-up at least 6 weeks after intervention, 2 (18%) patients exhibited low-grade heterotopic ossification reformation that was not clinically relevant and 9 (82%) did not show signs of heterotopic recurrence. Single-dose radiation therapy can help prevent the formation of heterotopic ossification in high-risk patients, acting as an effective adjunct to surgery in minimizing the risk of re-ulceration and re-amputation in the neuropathic patient.