The Look AHEAD trial was a multi-center, randomized controlled trial, to determine whether weight loss reduces cardiovascular morbidity and mortality in overweight individuals with type 2 diabetes. The objective of this study was to evaluate the incidence of severe hypoglycemia in patients enrolled in Look AHEAD. Research Design and Methods 5,145 subjects were randomized to diabetes support and education (DSE) or intensive lifestyle intervention (ILI). Instances of severe hypoglycemia were recorded. Regression analysis was used to compare the development of severe hypoglycemia between groups.Over the entire study, the severe hypoglycemia rate was not different between ILI and DSE groups (0.49 ILI, 0.51 DSE/100 person-years, rate ratio=1.12, p=0.41), but was greater in ILI during year 1 (p=0.008 for year by intervention interaction). During follow-up, severe hypoglycemia risk was higher with insulin, sulfonylurea or glitinide use at baseline (p<0.0001). The intervention effect differed by post-randomization insulin use (ILI to DSE HR=1.45 in insulin users versus HR=0.71 in non-users, p=0.009). Insulin use reduced by 3% in ILI in year 1. Compared to DSE, ILI participants in the lower 50% of weight loss in year 1 had similar percent insulin use and incident hypoglycemia, but ILI participants in the upper 50% of weight loss had lower percent insulin use and incident hypoglycemia.Reduction in insulin is necessary during intensive weight loss to avoid episodes of hypoglycemia. Although limited by self-reported evaluation of hypoglycemia, greater weight loss in ILI during year 1 was associated with reduced insulin use and lower rates of hypoglycemia later in the trial.