The aim of the present study was to determine the effectiveness of nonsurgical treatment for osteomyelitis of the hallucal sesamoids. Osteomyelitis of the hallucal sesamoids in young and healthy patients is rare and might originate from hematogenous spread or after a puncture wound. In diabetic patients with peripheral neuropathy, it often results from direct contiguous seeding from adjacent ulceration. The superiority of surgical versus nonsurgical therapy is still debated. In our institution, all patients presenting with osteomyelitis of the hallucal sesamoids are first treated nonsurgically but eventually usually require a surgical procedure. We reviewed 18 patients with a clinical and radiologic diagnosis of osteomyelitis of the hallucal sesamoids treated in our institution during a 13-year period (from January 2000 to December 2012). The inclusion criteria were a signal alteration on magnetic resonance imaging or bone lesions on computed tomography or conventional radiographs, combined with a deep ulcer with a positive probe-to-bone test. Nonsurgical therapy consisted of frequent wound treatment, immobilization, offloading in a cast or other orthotic device, and oral antibiotics. Of the 18 patients, 11 had diabetes, 16 had peripheral neuropathy, 11 had peripheral arterial disease, and 5 had immunosuppression. After a period of nonsurgical therapy ranging from 4 weeks to 9 months, 15 of 18 patients required surgical excision, internal resection, or amputation. In this patient population, we no longer consider nonsurgical therapy a viable option. Patients should be advised, before starting nonsurgical treatment, that the therapy will be long and demanding and very often results in a surgical procedure.