First line therapy of aplastic anemia with high dose cyclophosphamide causes toxicity and increased short-term mortality. We investigated cyclophosphamide at a lower "moderate" dose, in combination with aggressive supportive care, to determine if severe infections might be avoided and hematologic outcomes defined for this regimen. From 2010 to 2012, 22 patients received cyclophosphamide at 120 mg/kg plus cyclosporine, antibacterial, antiviral, and antifungal prophylaxis. Toxicity was considerable, mainly due to prolonged absolute neutropenia, which occurred regardless of pre-therapy blood counts and persisted an average of 2 months. Granulocyte transfusions for uncontrolled infection were required in 5, confirmed fungal infections documented in 6, and 9 patients died. Nine (41%) patients responded at 6 months. After a median follow-up of 2.2 years, relapse occurred in 2 and cytogenetic abnormalities were observed in 4 patients, including monosomy 7. Although cyclophosphamide has activity in SAA, its toxicity is not justified when far less dangerous alternatives are available. This trial was registered at www.clinicaltrials.gov as #NCT01193283.