RATIONALE, AIMS AND OBJECTIVES: Antipsychotics are approved treatment for severe conditions and have serious side effects. Antipsychotics are often prescribed off-label. Although a substantial proportion of antipsychotics are prescribed in primary care, it is largely unknown what motivates the general practitioner (GP) to initiate antipsychotic treatment. Therefore, we sought to examine the relation between pre-defined, licensed as well as off-label, reasons for antipsychotic treatment and the initiation of this treatment by the GP as well as report registration and incidence of antipsychotic treatment in general practice. METHODS: In a case-control study, 723 patients selected from an electronic database and with a new antipsychotic prescription were compared with 3615 controls receiving any other new prescription. Using logistic regression, six pre-defined categories of International Classification of Primary Care (ICPC) codes ('psychosis', 'depression and anxiety', 'sleeping disorders', 'acute stress and surmenage', 'dementia' and 'somatic indications') were associated with initiating antipsychotic treatment. RESULTS: All, including off-label, categories were significantly related to initiating antipsychotic treatment. The incidence of initiating antipsychotic therapy was 1.28 per 1000 persons per year (95% confidence interval: 1.09, 1.48). GPs registered an ICPC code in 50% and prescribed typical antipsychotics in 90% of the cases. Prescription of atypical antipsychotics increased almost threefold over the study period. CONCLUSIONS: The results suggest that GPs prescribe antipsychotics off-label. Despite serious side effects and relatively infrequent occurrence in Dutch general practices, GPs seem imprecise in underpinning and registrating the initiation of antipsychotic treatment. GPs increasingly prescribe atypical antipsychotics although the prescription of typical antipsychotics still dominates.