Diabetic foot infections (DFI) expanding to bones and joints are associated with a poor prognosis of limb salvage. The bactericidal epoxide fosfomycin accumulates in inflamed soft and bone tissue, and may represent a potential treatment option for targeting severe DFI. Fifty-two patients (35 men, 17 women, mean age 62.9 +/- SD 9.2 years) with limb-threatening DFI (that is, Wagner grade 3 and higher) were enrolled in a multi-center compassionate use program of fosfomycin. Twenty-two patients (42.4%) had unsuccessfully been pretreated with other antimicrobials. Besides standard treatment (topical wound care and surgical debridement), eligible subjects received a combination of 8 to 24 g fosfomycin daily, and a conventional antibiotic agent, usually a beta-lactam compound. Treatment duration averaged 14.4 +/- 8.3 days. Limb-sparing surgery was possible in 48 patients (92.3%, 95% confidence interval 81.5-97.9%). Only four participants faced mild drug-related side effects (nausea, rash). Logistic regression analysis showed a trend towards better results with prolonged treatment, whereas a dose increase above 12 g daily did not affect outcomes. In DFI being resistant to conventional antibiotic agents, intravenous fosfomycin offers an effective treatment choice that may increase the likelihood of limb preservation. The present data warrant a larger comparative trial to stabilize effect estimates.