Background Common deterrents to insulin therapy for both physicians and patients are the complexity and burden of daily injections. In January 2006, the first inhaled human insulin (INH, Exubera® (insulinhuman [rDNA origin])InhalationPowder) was approved for use in adult patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) in the United States and European Union. Results from the INH clinical trial program have shown comparable efficacy of INH to subcutaneous (SC) insulin and superior efficacy versus oral antidiabetic agents; thus providing effective glycemic control in adult patients with T2DM without the requirement for preprandial injections. However, because subjects in those trials were randomized to either INH or an alternative, the studies could not estimate the effect of INH on patient acceptance of insulin therapy. Therefore, traditional study designs cannot provide answers to important and practical questions regarding real world effectiveness, which is influenced by psychological and other access barriers. Methods To overcome these limitations, the Real World Trial was designed to estimate the effect of the availability of INH as a treatment option for glycemic control. A total of approximately 700 patients from Canada, France, Germany, Italy, Spain, United Kingdom, and the United States with T2DM poorly controlled by oral agent therapy will be randomized to two different treatment settings. Patients and clinicians in both groups (A & B) may choose from all licensed therapies for diabetes including SC insulin delivered by pens; INH will be an additional treatment option only available in Group A. The Real World Trial (Protocol A2171018) has been registered with ClincalTrials.gov, registration id NCT00134147. Results The primary outcome for the trial will be the difference in mean glycosylated hemoglobin (HbA1c) at 6 months between groups. The design was based on a preceding feasibility study examining the theoretical effects of inhaled insulin availability on treatment choice in 779 patients. In that study, patients were three times more likely to choose insulin therapy when inhaled insulin was available. Conclusion Innovations in study designs may provide an opportunity to reveal unbiased answers to important treatment questions that are more relevant to prescribers, funding agencies, and healthcare policymakers.