OBJECTIVES: To evaluate the association between use of antipsychotics and risk of stroke in patients with cardiovascular diseases (CVDs). METHODS: This was a retrospective nested case-control study analyzing data from the National Health Insurance Research Database in Taiwan. A cohort of all patients with CVDs initiating an antipsychotic was identified during January 1, 1998 and December 31, 2006. Cases were defined as those with hospitalizations for stroke (ICD9-CM codes 430-438, A-code A29), and the date of stroke admission was referred as the index date. Using the incidence density sampling approach, each case was matched to ten randomly-selected controls on age (± 5 years), sex and cohort entry date (± 365 days). Controls were assigned the same index date as their corresponding case. Use of antipsychotics was measured during a six-month period before the index date and categorized into typical or atypical class. Conditional logistic regressions were used to estimate odds ratios (ORs). RESULTS: The study cohort comprised 6773 CVD patients, from which 533 cases and 5057 matched controls were identified. Any use of atypical antipsychotics was associated with an increased risk of stroke when compared with typical antipsychotics (adjusted OR, 1.46; 95 % CI, 1.01-2.10). Additionally, the comparative risk was increased to a greater extent as atypical antipsychotics were prescribed within 90 days before the index date (adjusted OR, 1.94; 95% CI, 1.34-2.83). Further stratified analyses indicated that any use of atypical antipsychotics was associated with a 1.55-fold increased risk of stroke in the elderly population. CONCLUSIONS: Use of atypical antipsychotics is associated with an increased risk of stroke relative to typical antipsychotics among patients with CVDs, and the risk is further increased as atypical antipsychotics are prescribed more currently. Clinicians should be aware of the stroke risk while prescribing antipsychotics for patients with underlying CVDs, especially in the elderly.