Abstract: Objective To investigate the association of the activity of insulin degrading enzyme (IDE) with cognitive deficits in T2DM patients. Methods Eighty patients in Tangshan Gongren Hospital and 80 controls without T2DM from the Medical Examination Center between May 2015 and July 2015 were recruited. The data on demographic characteristics (including gender, age, education, duration of illness and BMI) and clinical parameters (including FPG, FIN, HbA1c, TC, TG, LDL-C, HDL-C, hs-CRP and Hcy) were collected. IDE was measured by IDE Immunoca Pture Act. Cognitive performance was assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) which consists of five subtests including immediate memory, visuospatial constructional, language, attention and delayed memory; and the scores from the above five subtests are scaled together to create a total score. Difference in RBANS scores was compared between the T2DM group and control group. T2DM patients were divided into high-IDE-activity group and low-IDE-activity group according to the median level of IDE activity, and the difference in cognitive function was compared between the two groups. Results Serum FPG, HbA1c, TC, TG, LDL-C, hs-CRP, Hcy and HOMA-IR levels, and BMI of the T2DM patients were higher than those of the controls; and duration of illness was longer and the activity of IDE were lower than that of the controls (P < 0.05). Age, gender, education, SBP, DBP and serum HDL-C were similar in both groups (P > 0.05). RBANS scores were lower in the T2DM patients than in the controls on the total score and all subtests (P < 0.05) expect for constructional of RBANS. In the T2DM patients, immediate memory, visuospatial/constructional, language, attention, delayed memory and total score of the patients with high IDE were higher than those of the patients with low IDE (P < 0.01). Stepwise regression analysis showed that the activity of IDE inversely correlated with IR; and the activity of IDE positively correlated with immediate memory, visuospatial/constructional, language, attention, delayed memory and total score in the T2DM patients (P < 0.01). Conclusions Decreased activity of IDE may be one of the risk factors of cognitive deficits in T2DM patients.