Objective To examine the relationship of cognitive performance to exposure to insulin (INS) and thiazolidinediones (TZD) in the ACCORD-MIND cohort. Methods Participants (55-80 years) with type 2 diabetes (T2D), hemoglobin A1c (HbA1c) > 7.5% (> 58 mmol/mol), and a high risk of cardiovascular events were randomly assigned to receive intensive control targeting HbA1c to < 6.0% (42 mmol/mol) or a standard strategy targeting HbA1c to 7.0%-7.9% (53-63 mmol/mol). The Digit Symbol Substitution Test (DSST) was assessed at baseline and at 20 and 40 months. Exposure to INS was calculated as average daily dose/kg of body weight; exposure to rosiglitazone (ROS) was calculated as days of ROS prescription in the intervals preceding the 20- and 40-month DSSTs. Results At baseline, INS use was associated with reduced DSST performance, but not after controlling for comorbidities and lab values. There was no relationship between use of a TZD and DSST performance on at baseline. ROS but not INS exposure was associated with greater decline in DSST performance over 40 months in subjects randomized to the intensive but not the standard group. Conclusions Exposure to a TZD may increase cognitive decline in some patients with T2D. However, these results may be confounded by unexplained differences between participants.