In addition to the global use of organophosphate (OP) pesticides for agriculture, OP nerve agents and pesticides have been employed on battlefields and by terrorists (e.g., a recent sarin attack in Syria). These occurrences highlight the need for an effective countermeasure against OP exposure. Human butyrylcholinesterase (HuBChE) is a leading candidate, but injection of the high doses required for protection present pharmacokinetic challenges. An aerosolized recombinant form (aer-rHuBChE) that can neutralize inhaled OPs at the portal of entry has been assessed for its efficacy in protecting macaques against respiratory toxicity following inhalation exposure to the pesticide paraoxon (aer-Px). While protection in macaques has been demonstrated using the MicroSprayer® delivery device, administration to humans will likely employ a vibrating mesh nebulizer (VMN). Compared to the 50–70% lung deposition achieved in adult humans with a VMN, deposition in macaques is <5%, an initial major obstacle to demonstrating protection. Such problems have been partly overcome by using a more efficient modified VMN and proportionally higher doses, which together generate an effective rHuBChE pulmonary bioshield and protect against high levels of inhaled Px.