Cohort studies suggest that exposure to antipsychotic agents may be associated with an increased risk of venous thromboembolism (VTE). Few data concerning antidepressant drugs are available. Using a different methodological approach, the aim of this study was to estimate the association between neuroleptic and antidepressant drug use and the risk of VTE. We report the results of a case-control study designed to evaluate interactions between acquired and inherited risk factors of VTE. We included 677 cases hospitalized with deep vein thrombosis and or pulmonary embolism with no major acquired risk factor for VTE, and 677 controls matched for gender and age. Drug exposure was defined as current use of drugs at admission. Neuroleptic exposure was associated with an increased risk of VTE (OR = 2.1, 95% CI 1.4-3.2). Among neuroleptics, antipsychotic agent use was associated with a 3.5-fold increased risk of VTE (OR = 3.5, 95% CI 2.0-6.2). No association was found between antidepressant drug exposure and the risk of VTE (OR = 1.1, 95% CI 0.9-1.5). In this hospital-based case-control study, exposure to antipsychotic drugs was associated with an increased risk of VTE. These results, added to previous results, suggest that clinicians should consider antipsychotic drug exposure as a potential risk factor of VTE. More studies are needed in order to further elucidate this adverse effect, and to determine the possible predisposing factors and the biological mechanisms involved.