Early and targeted antimicrobial therapy improves outcomes in patients with febrile neutropenia (FN). We evaluated the impact of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) on antimicrobial utilization in the management of FN. A cohort of patients with FN and hematological malignancy was identified. Cases (in whom FDG-PET was performed, n = 37) were compared with controls (in whom conventional investigations excluding FDG-PET were performed, n = 76). An underlying cause for FN was determined in 94.6% of cases, compared to 69.7% of controls. FDG-PET had a significant impact on antimicrobial utilization compared to conventional imaging (35.1% vs. 11.8%; p = 0.003), and was associated with shorter duration of liposomal amphotericin-B therapy for systemic fungal infection (median 4.0 days cases vs. 10.0 days controls; p = 0.001). Cases had a longer length of hospitalization (p = 0.016). In the management of patients with high-risk FN, FDG-PET improves diagnostic yield and allows rationalization of antifungal therapy. The impact upon healthcare costs associated with antimicrobial therapy for FN requires further evaluation.