Intensification of glycemic control is associated with weight gain, however, less is known about weight change during the maintenance phase of glycemic management. On the basis of current models of energy homeostasis, we hypothesize that insulin use will result in less weight gain than oral antidiabetic agents in patients with well-controlled diabetes. This is a prospective cohort nested within a randomized control trial at an academic clinic, with enrollment from June 2002 to January 2005. A total of 163 patients with type 2 diabetes were enrolled after obtaining glycemic control. Insulin use was assessed by self-report at baseline. Participants were weighed at baseline and five follow-up visits over 24 months. The weight change was compared between insulin users and noninsulin users. The average (s.d.) age was 55 (11), 44% are female and 21% are black. The median duration of diabetes was 5 (0.5-10) years. At baseline, 88 participants (54%) reported insulin use with an average of 69 (6) units/day. Baseline BMI in the insulin users was 35 (6) and 33 (6) in noninsulin patients. Over 24 months, noninsulin patients gained 2.3 additional kilograms compared with insulin users (2.8 kg (6.8) vs. 0.5 kg (6.5), P = 0.065). After adjusting for age, race, sex, baseline weight, intervention status, and change in A1C, insulin users had 2.5 kg less weight gain than noninsulin users (P = 0.033). Less weight gain was observed over 24 months in insulin-treated patients. Whether this effect may be due to central catabolic effects of insulin merits additional confirmatory study and mechanistic investigation.