Patients with low-risk neutropenic fever as defined by the Multinational Association of Supportive Care in Cancer (MASCC) score might benefit from ambulatory treatment. Optimal management remains to be clearly defined, and new oral antibiotics need to be evaluated in this setting. Cancer patients with febrile neutropenia and a favorable MASCC score were randomized between oral moxifloxacin and intravenous ceftriaxone. All were fit for early hospital discharge. The global success rate was related to the efficacy of monotherapy, as well as to the success of ambulatory monitoring. The trial was closed prematurely because of low accrual. Ninety-six patients were included (47 in the ceftriaxone arm and 49 in the moxifloxacin arm). A total of 65% were women, 30.2% had lymphoma, 34.4% had metastatic, and 35.4% had non-metastatic solid tumors. The success rates of home antibiotics were 73.9% and 79.2% for ceftriaxone and moxifloxacin, respectively. Seven patients were not discharged, and 14 required re-hospitalization. There were 17% of microbiologically documented infections that were, in most cases, susceptible to oral monotherapy. These results suggest that MASCC is a valid and useful tool to select patients for ambulatory treatments and that oral moxifloxacin monotherapy is safe and effective for the outpatient treatment of cancer patients with low-risk neutropenic fever.