OBJECTIVE—This study, one of the first to address issues of pulmonary insulin delivery in smokers, compared pharmacokinetics of inhaled insulin delivered via the AERx insulin Diabetes Management System (iDMS) in nondiabetic cigarette smokers and nonsmokers. RESEARCH DESIGN AND METHODS—In this randomized two-period crossover efficacy and safety trial in 27 nondiabetic smokers and 16 nonsmokers (18 men/25 women, mean age 28 years, mean BMI 23.0 kg/m2), subjects received single doses of inhaled insulin (33.8 IU) following overnight fasting on consecutive dosing days. On one dosing day, smokers smoked three cigarettes immediately before insulin administration (“acute smoking”); on the other dosing day, smokers had not smoked since midnight (“nonacute smoking”). After inhalation, 6-h serum insulin and serum glucose profiles were determined. RESULTS—Pharmacokinetic results for evaluable subjects were derived from serum insulin profiles. The amount of insulin absorbed during the first 6 h after dosing (area under the exogenous serum insulin curve from 0 to 6 h [AUC(0–6 h)]) was significantly greater in smokers (63.2 vs. 40.0 mU · l−1 · h−1, P = 0.0017); peak concentration was both higher and earlier in the smokers (maximal serum concentration of insulin [Cmax] 42.0 vs. 13.9 mU/l, P < 0.0001; time to maximal serum concentration of insulin [tmax] 31.5 vs. 53.9 min, P = 0.0003). The estimated intrasubject variability of AUC(0–6 h) was 13.7 and 16.5% for nonsmokers and smokers, respectively. No safety issues arose. CONCLUSIONS—Absorption of inhaled insulin via the AERx iDMS was significantly greater in smokers, with a higher AUC(0–6 h) and Cmax and a shorter tmax. Intrasubject variability of AUC(0–6 h) was low and similar in nonsmokers and smokers. These data prompt more extensive investigation of inhaled insulin in diabetic smokers.