BACKGROUND: There is increasing evidence that outpatient parenteral antimicrobial therapy (OPAT) is overused for children and that outcomes with oral therapy are equivalent. Our objective was to compare economic burden between OPAT and oral therapy, accounting for direct and indirect costs and caregiver quality of life (QoL). METHODS: We conducted a prospective cohort study of caregivers for children after hospitalization who were treated with prolonged antimicrobial therapy. We collected data about missed work and school and time spent administering therapy. Caregivers completed the Pediatric Quality of Life Inventory to assess QoL. Clinical information included length of stay, treatment indication, and type of therapy (OPAT versus oral therapy). Direct medical costs were obtained by using a microcosting system and accounted for medication, supplies, and homenursing visits. The primary cost outcome was the mean daily cost of therapy. Multivariable models were developed to adjust for potential confounders. RESULTS: Two hundred and twelve caregivers completed surveys: 123 (58%) for oral therapy and 89 (42%) for OPAT. Caregivers administering OPAT reported more missed work, missed school for their children, time with daily medication administration (90 vs 6 minutes; P , .01) and lower QoL scores (77.8 vs 68.9