Rationale: Few noninvasive biomarkers for pulmonary inflammation are currently available that can assess the lung-specific response to anti-inflammatory treatments. Positron emission tomography with [¹⁸F]fluorodeoxyglucose (FDG-PET) is a promising new method that can be used to quantify pulmonary neutrophilic inflammation. Objective: To evaluate the ability of FDG-PET to measure the pulmonary anti-inflammatory effects of hydroxymethyl-glutaryl coenzyme A reductase inhibitors (statins) and recombinant human activated protein C (rhAPC) in a human model of experimentally-induced lung inflammation. Methods: Eighteen healthy volunteers were randomized to receive placebo, lovastatin, or rhAPC before intrabronchial segmental endotoxin challenge. FDG-PET imaging was performed before and after endotoxin instillation. The rate of [¹⁸F]FDG uptake was calculated as the influx constant K_i by Patlak graphical analysis. Bronchoalveolar lavage (BAL) was performed to determine leukocyte concentrations for correlation with the PET imaging results. Measurements and Main Results: There was a statistically significant decrease in K_i in the lovastatin-treated group that was not seen in the placebo-treated group, suggesting attenuation of inflammation by lovastatin treatment despite a small decrease in BAL total leukocyte and neutrophil counts that was not statistically significant. No significant decrease in K_i was observed in the rhAPC-treated group correlating with a lack of change in BAL parameters, indicating no significant anti-inflammatory effect with rhAPC. Conclusion: FDG-PET imaging is a sensitive method for quantifying the lung-specific response to anti-inflammatory therapies and may serve as an attractive platform for assessing the efficacy of novel anti-inflammatory therapies at early phases in the drug development process. Clinical Trial Registry Information: ID# NCT00741013 at www.clinicaltrials.gov