OBJECTIVE: We sought to compare and evaluate the impact of inhaled versus injected insulin on potential mediators of patient acceptance of insulin therapy while maintaining comparable A1C levels. RESEARCH DESIGN AND METHODS: During a noninferiority efficacy trial conducted in 40 centers in the U.S., we surveyed treatment satisfaction, quality of life, and adherence barriers at weeks -4, -1, 6, 12, 20, and 24 in adolescents aged 12-17 years and adults with type 1 diabetes who received premeal regular plus twice-daily NPH insulin during a 4-week run-in; then, subjects were randomized to premeal inhaled human insulin plus twice-daily NPH (adults, n = 102; adolescents, n = 60) (inhaled) or remaining on run-in therapy (n = 105 and 60, respectively) (subcutaneous injection). RESULTS: Overall treatment satisfaction (0-100) increased by 13.2 +/- 1.1 units for inhaled insulin (baseline = 63.3 +/- 1.2) compared with 1.7 +/- 0.8 for subcutaneous insulin injection (baseline = 64.1 +/- 1.2, P < 0.0001). All 12 satisfaction subscales favored inhaled insulin (all P < 0.01), and effects did not vary by age or sex. Despite similar baseline-adjusted end point A1C for inhaled (7.7 +/- 0.1%) and subcutaneous (7.9 +/- 0.1%) regimens, quality-of-life scales of mental health, symptoms, health status, cognitive functioning, and adherence barriers during treatment were more favorable for inhaled insulin (all P < 0.05). Greater satisfaction was associated with fewer barriers to insulin adherence (rho = -0.78, P < 0.0001) and a greater reduction in A1C (rho = -0.18, P < 0.001). CONCLUSIONS: Treatment satisfaction was substantially more favorable, adherence barriers moderately lower, and quality of life moderately higher for inhaled compared with subcutaneous regimen. It remains to be demonstrated whether these patient-reported outcomes will translate into improved adherence and glycemic control.