Adult diabetic patients admitted to our Diabetes Center from September 1996 to January 1998 for severe, limb-threatening foot infection were consecutively enrolled in a prospective, randomized, controlled clinical study aimed at assessing the safety and efficacy of recombinant human granulocyte colony-stimulating factor (G-CSF) (lenograstim) as an adjunctive therapy for the standard treatment of diabetic foot infection. Forty patients, all of whom displayed evidence of osteomyelitis and long-standing ulcer infection, were randomized 1:1 to receive either conventional treatment (i.e., antimicrobial therapy plus local treatment) or conventional therapy plus 263 µg of G-CSF subcutaneously daily for 21 days. The empiric antibiotic treatment (a combination of ciprofloxacin plus clindamycin) was further adjusted, when necessary, according to the results of cultures and sensitivity testing. Microbiologic assessment of foot ulcers was performed by both deep-tissue biopsy and swab cultures, performed at enrollment and on days 7 and 21 thereafter. Patients were monitored for 6 months; the major endpoints (i.e., cure, improvement, failure, and amputation) were blindly assessed at weeks 3 and 9. At enrollment, both patient groups were comparable in terms of both demographic and clinical data. None of the G-CSF-treated patients experienced either local or systemic adverse effects. At the 3- and 9-week assessments, no significant differences between the two groups could be observed concerning the number of patients either cured or improved, the number of patients displaying therapeutic failure, or the species and number of microorganisms previously yielded from cultures at day 7 and day 21. Conversely, among this small series of patients the cumulative number of amputations observed after 9 weeks of treatment appeared to be lower in the G-CSF arm; in fact, only three patients (15%) in this group had required amputation, whereas nine patients (45%) in the other group had required amputation (P = 0.038). In conclusion, the administration of G-CSF for 3 weeks as an adjunctive therapy for limb-threatening diabetic foot infection was associated with a lower rate of amputation within 9 weeks after the commencement of standard treatment. Further clinical studies aimed at precisely defining the role of this approach to this serious complication of diabetes mellitus appear to be justified.