PURPOSE. To describe a method of drug delivery to the retina via aerosolized nanoparticles in the gas phase during the gas-exchange stage of vitrectomy in a porcine model. METHODS. An ultrasonically atomized and dried sodium fluorescein aerosol was produced with a concentration of 12 ng/mL and a mass median particle size of 407 nm. Eighteen porcine eyes were randomly divided into six groups and subjected to standard three-port pars plana vitrectomy. After the air-fluid exchange and during the gas exchange, the eyes were exposed to the aerosol, either as a steady flow through the chamber (3-6 μg/min) or as a single fill (50 ng) at three exposure times (three eyes/time point). RESULTS. The flow-through delivery mode provided a relatively uniform deposition of aerosol on the inner surface of the retina, and longer delivery time led to an increase in the quantity deposited, with greater than 40 ng total deposition by 10 minutes. The single-fill method had uniform deposition but lower total delivery, approximately 10 ng by 60 minutes. Modeling of the data suggests that deposition in the flow-through mode is successful if the vitreous chamber contents are well mixed. The single-fill delivery was described by diffusion in a quiescent state. CONCLUSIONS. This study demonstrates a novel method of drug delivery to the posterior pole by using aerosolized nanoparticles that may be used in the gas phase of vitrectomy. Therapeutic applications include antimetabolites for modulation of proliferative vitreoretinopathy, antimicrobial agents for endophthalmitis, antiangiogenic compounds for vasoproliferative disorders, corticosteroid delivery, and other pharmacotherapies directed at the retina and choroid.