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Objective: The risk of hypoglycemia in people with insulin-treated diabetes has debarred them from certain "safety-critical" occupations, including flying commercial aircraft. This report evaluates the effectiveness of a protocol enabling a large cohort of insulin-treated pilots to fly commercially., Research Design and Methods: This was an observational study of pilots with insulin-treated diabetes who were granted medical certification to fly commercial and noncommercial aircraft. Clinical details, pre- and in-flight (hourly and 30 min before landing) blood glucose values were correlated against the protocol-specified ranges: green (5-15 mmol/L), amber (low, 4-4.9 mmol/L; high, 15.1-20 mmol/L), and red (low, <4 mmol/L; high, >20 mmol/L)., Results: A total of 49 pilots with type 1 (84%) or type 2 (16%) diabetes who had been issued class 1 or class 2 certificates were studied. Median diabetes duration was 10.9 years. Mean HbA 1c was 7.2% (55.0 mmol/mol) before certification and 7.2% (55.1 mmol/mol) after certification ( P = 0.97). Blood glucose values ( n = 38,621) were recorded during 22,078 flying hours. Overall, 97.69% of measurements were within the green range, 1.42% within the low amber range, and 0.75% within the high amber range. Only 0.12% of readings were within the low red range and 0.02% within the high red range. Out-of-range readings declined from 5.7% in 2013 to 1.2% in 2019. No episodes of pilot incapacitation occurred, and glycemic control did not deteriorate., Conclusions: The protocol is practical to implement, and no events compromising safety were reported. This study represents what is, to our knowledge, the most extensive data set from people with insulin-treated diabetes working in a "safety-critical" occupation, which may be relevant when estimating risk in other safety-critical occupations., (© 2020 by the American Diabetes Association.)