We investigated the ability of the engineered paraoxonase-1 variants G3C9, VII-D11, I-F11 and VII-D2 to afford protection against paraoxon intoxication. Paraoxon is the toxic metabolite of parathion, a common pesticide still in use in many developing countries. An in vitro investigation showed that VII-D11 is the most efficient variant at hydrolyzing paraoxon for the enzyme expressed via adenovirus infection of 293A cells and mice, respectively. Compared to the G3C9 parent scaffold, VII-D11 is 15-20 fold more efficacious at hydrolyzing paraoxon. Coinciding with these results, mice expressing VII-D11 in their blood survived and showed no symptoms against a cumulative 6.3 LD50 dose of paraoxon while mice expressing G3C9 experienced tremors and only 50% survival. We then determined whether VII-D11 can offer protection against paraoxon when present at substoichiometric concentrations. Mice containing varying concentrations of VII-D11 in their blood (0.2 - 4.1 mg/mL) were challenged with doses of paraoxon at fixed stoichiometric ratios that constitute up to a ten-fold molar excess of paraoxon to enzyme (1.4 - 27 LD(sub50) doses) and were assessed for tremors and mortality. Mice were afforded complete asymptomatic protection below a paraoxon to enzyme ratio of 8:1, whereas higher ratios produced tremors and/or mortality. VIID11 in mouse blood co-eluted with high density lipoprotein, suggesting an association between the two entities. Collectively, these results demonstrate that VII-D11 is a promising candidate for development as a prophylactic catalytic bioscavenger against organophosphorous pesticide toxicity.