Objective: To examine the association between antipsychotic use and the risk of acute coronary syndrome (ACS) in elderly de novo users of antipsychotics. Design: A community-based nested case-control study. Setting: Pharmacy dispensing records from community pharmacies in The Netherlands were linked to hospital discharge records of 950 000 community-dwelling residents from 1998 to 2008. Patients: Cases were 2803 patients aged 60 years or older, with a first hospital admission for ACS identified within a cohort of 26 157 elderly persons with at least one antipsychotic prescription (de novo users). For each case, four controls with no hospitalisation for ACS (n=11 024) were randomly selected from the same cohort, matched by age, gender and duration of registration in the database. Main outcome measures: Relative risks, expressed as ORs, for ACS associated with antipsychotic drug use adjusted for comorbidity. Results: Current exposure to antipsychotics was associated with a decreased risk of hospitalisation for ACS compared with past users (adjusted OR 0.5, 95% CI 0.5 to 0.6). Cumulative use up to 100 Defined Daily Doses was also associated with a decreased risk of hospitalisation (OR 0.7, CI 0.6 to 0.8). No differences in risk were found between typical and atypical antipsychotics, current dosage or different degrees of serotonergic, histaminergic or adrenergic affinity of the antipsychotic. Conclusions: A decreased risk of hospitalisation for ACS in elderly patients currently using antipsychotics was found. Further research is needed to confirm our results and to determine whether there is a cardioprotective effect or a high non-referral rate in elderly antipsychotic users with ACS.