OBJECTIVE: To assess the impact of the development of high- or low-affinity insulin antibodies (IABs) on postprandial glucose tolerance, duration of insulin action, and clinical safety in patients with type 1 diabetes receiving inhaled insulin (Exubera). RESEARCH DESIGN AND METHODS: This study consisted of a prospective, randomized, open-label, parallel-group trial in which 47 patients with type 1 diabetes received NPH insulin twice daily plus either premeal inhaled insulin (INH group; n = 24) or pre-meal subcutaneous regular insulin (SC group; n = 23) for 24 weeks. Meal challenge and euglycemic clamp studies were performed on consecutive days at baseline, week 12, and week 24. Adverse events were monitored. RESULTS: For the INH and SC groups, mean (+/-SD) IAB levels were 3.5 +/- 3.9 and 2.6 +/- 4.1 muU/ml at baseline, respectively, compared with 101.4 +/- 140.4 and 4.3 +/- 9.4 microU/ml at week 24. At week 24, the changes from baseline were similar for the INH and SC groups for maximal plasma glucose concentration (C(max)) (adjusted ratio for treatment group difference 0.99 [90% CI 0.95-1.03]), area under the plasma glucose concentration time curve (adjusted ratio for treatment group difference 0.98 [0.88-1.08]), and duration of insulin action (adjusted treatment group difference 29 min [-49 to 108]). No adverse events were attributed to IABs. CONCLUSIONS: In patients with type 1 diabetes treated with inhaled insulin, development of high- or low-affinity IABs did not impair postprandial glucose tolerance, alter the time-action profile of insulin, or impact tolerability. No clinical relevance of IABs was identified in this study.