Pioglitazone is a PPARg agonist commonly prescribed for the clinical treatment of diabetes. We sought to expand its use to lung cancer prevention in a benzo[a]pyrene (B[a]P) mouse model with direct lung delivery via inhalation. Initially, we conducted inhalational toxicity experiments with 0, 15, 50, 150, and 450 mg/kg body weight/day pioglitazone in 40 A/J mice. We examined the animals for any physical toxicity and bronchoalveolar lavage fluids for inflammatory and cytotoxicitymarkers. Doses up to and including 450 mg/kg bw/d failed to demonstrate toxicity with aerosol pioglitazone. For chemoprevention experiments, A/J mice were randomized to treatment groups of inhaled doses of 0, 50, 150, or 450 mg/kg bw/d pioglitazone 1 or 8 weeks after the last dose of B[a]P. For the early treatment group, we found up to 32% decrease in lung adenoma formation with 450 mg/kg bw/d pioglitazone. We repeated the treatments in a second late-stage experiment and found up to 44% decreases in lung adenoma formation in doses of pioglitazone of 150 and 450 mg/kg bw/day. Both the early-And the late-stage experiments demonstrated biologically relevant and statistically significant decreases in adenoma formation. We conclude that aerosol pioglitazone is well-Tolerated in the A/J mouse model and a promising chemoprevention agent for the lower respiratory tract.