Aims: To determine the baseline characteristics and glucose-lowering therapies associated with weight change among patients with type 2 diabetes. Methods: Eleven thousand one hundred and forty participants in the ADVANCE trial were randomly assigned to an intensive [aiming for a haemoglobin A1c (HbA1c) ≤6.5%] or a standard blood glucose-control strategy. Weight was measured at baseline and every 6 months over a median follow-up of 5 years. Multivariable linear regression and linear-mixed effect models were used to examine predictors of weight change. Results: The mean difference in weight between the intensive and standard glucose-control arm during follow-up was 0.75 kg (95% CI: 0.56-0.94), p-value <0.001. The mean weight decreased by 0.70 kg (95% CI: 0.53-0.87), p < 0.001 by the end of follow-up in the standard arm but remained stable in the intensive arm, with a non-significant gain of 0.16 kg (95% CI: -0.02 to 0.34), p = 0.075. Baseline factors associated with weight gain were younger age, higher HbA1c, Caucasian ethnicity and number of glucose-lowering medications. Treatment combinations including insulin [3.22 kg (95% CI: 2.92-3.52)] and thiazolidinediones [3.06 kg (95% CI: 2.69-3.43)] were associated with the greatest weight gain while treatment combinations including sulphonylureas were associated with less weight gain [0.71 kg (95%CI: 0.39-1.03)]. Conclusions: Intensive glucose-control regimens are not necessarily associated with substantial weight gain. Patient characteristic associated with weight change were age, ethnicity, smoking and HbA1c. The main treatment strategies predicting weight gain were the use of insulin and thiazolidinediones.