The association between antipsychotic use and the risk of stroke in schizophrenic patients is controversial. We sought to study the association in a nationwide cohort with schizophrenia.Using a retrospective cohort of patients with schizophrenia (N = 31,976) derived from the Taiwan National Health Insurance Research Database, 802 new-onset cases of stroke were identified within 10 years of follow-up (from 2000 through 2010). We designed a case-crossover study using 14-day windows to explore the risk factors of stroke and the association between antipsychotic drugs and the risk of stroke. We analyzed the risks of individual antipsychotics on various subgroups of stroke including ischemic, hemorrhagic, and other strokes, and the risks based on the antipsychotic receptor-binding profile of each drug.Use of any second-generation antipsychotic was associated with an increased risk of stroke (adjusted risk ratio = 1.45, P = .009) within 14 days while the use of any first-generation antipsychotic was not. Intriguingly, the use of any second-generation antipsychotic was associated with ischemic stroke but not hemorrhagic stroke. The antipsychotic receptor-binding profile analysis showed that the antihistamine 1 receptor was significantly associated with ischemic stroke (adjusted risk ratio = 1.72, P = .037), and the sensitivity analysis based on the 7-day window of exposure validated the association (adjusted risk ratio = 1.87, P = .015).Use of second-generation antipsychotic drugs appeared to be associated with an increased risk of ischemic stroke in the patients studied, possibly mediated by high affinity for histamine-1 receptor blockade. Further research regarding the underlying biological mechanism and drug safety is suggested.