AIMS: Intensive glucose control, often involving insulin treatment, failed to improve cardiovascular outcomes in several clinical trials. Observational studies reported an association between insulin use and cardiovascular disease (CVD) risk. It hatherefore been suggested that insulin adversely affects CVD risk. To investigate the feasibility of this hypothesis, we studied the association between insulin dose and CVD risk in type 2 diabetes. METHODS: A case-control study was conducted of new users of oral antidiabetics who were prescribed insulin, using the Dutch Pharmo database. Cases were hospitalized for a cardiovascular event (CVE) and matched 1:2 to patients who were not hospitalized for a CVE, by sex, age, duration of diabetes and type oforal antidiabetic. Patients were divided into tertiles according to mean daily insulin dose. Conditional logistic regression analyses were used to explore the association between insulin exposure and CVE risk. RESULTS: We included 836 patients (517 (62%)male, mean age 66 years). After adjusting for available potential confounders, including HbA1c and triglycerides, insulin exposure was positively related to CVE risk (odds ratios for high (>/=53.0 U/day) and intermediate (24.3-52.9 U/day) vs. low exposure (