Background: An adjunctive topical therapy with gentamicin-sponges to systemic antibiotic therapy might improve the healing of infected diabetic foot ulcers (DFUI). Methods: Single-center, investigator-blinded pilot study, randomizing (1:1) the gentamicin-sponge with systemic antibiotic versus systemic antibiotics alone for patients with DFUI. Results: We included 88 DFUI episodes with 43 patients in the gentamicin-sponge arm and 45 in the control arm. Overall, 64 (64/88; 73%) witnessed total clinical cure, 13 (15%) significant improvement, and 46 (52%) showed total eradication of all pathogens at the final visit. Regarding final clinical cure, there was no difference in favour of the gentamicin-sponges (26/45 vs. 31/43; p = 0.16). However, the gentamicin-sponge arm tended to a more rapid healing. In multivariate analysis adjusting for the case-mix, the variable “gentamicin-sponge” was not significantly associated with “cure and improvement”. Gentamicin-sponges were very well tolerated, without any attributed adverse events. Conclusions: The gentamicin-sponge was very well tolerated, but did not significantly influence overall cure.