The times and costs required for four methods of reconstituting i.v. antibiotic doses in drug manufacturers' piggyback bottles (DMPBs) were compared. Instafil filling devices were used with (1) a pressure cuff (Instafil Instafusor) for the diluent bag, (2) a peristaltic pump (Wheaton Unispense), and (3) a vacuum line. The fourth method used a vacuum line and a control handle (Vacu-fil, American McGaw). Batches of 20 bottles filled to 50 mL and 20 bottles filled to 100 mL (three trials each) and 60 bottles filled to 100 mL (two trials) were prepared by each of the four methods. The Instafil with vacuum line was significantly faster than the other methods used to fill batches of 20 DMPBs with 50 mL and 100 mL of diluent. It was also significantly faster than the Vacu-fil and the Instafil with the cuff for filling batches of 60 DMPBs with 100 mL of diluent. For batches of 60 DMPBs, the fill times for the Instafil with vacuum line and the Instafil with the peristaltic pump were not significantly different. For the batches of 20 50-mL DMPBs, overall cost per dose for the Instafil with vacuum line was $0.36, followed by Instafil with the pump ($0.37), Instafil with cuff ($0.38), and Vacu-fil ($0.54). Other batch sizes and fill volumes ranked similarly. Of the methods tested, the Instafil device with a vacuum line was the most efficient and cost-effective for preparing batches of 20 to 60 i.v. antibiotic doses in manufacturers' piggyback bottles.