The primary objective of this study was to determine if second generation antipsychotic (SGA) administration was associated with lower aggressiveness scores compared to first generation (FGA). The secondary objective was to determine if antidepressants, mood stabilizers and benzodiazepines administration were respectively associated with lower aggressiveness scores compared to patients who were not administered these medications. 331 patients with schizophrenia (n = 255) or schizoaffective disorder (n = 76) (mean age = 32.5 years, 75.5 % male gender) were systematically included in the network of FondaMental Expert Center for Schizophrenia and assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders and validated scales for psychotic symptomatology, insight and compliance. Aggressiveness was measured by the Buss-Perry Aggression Questionnaire (BPAQ) score. Ongoing psychotropic treatment was recorded. Patients who received SGA had lower BPAQ scores than patients who did not (p = 0.01). More specifically, these patients had lower physical and verbal aggression scores. On the contrary, patients who received benzodiazepines had higher BPAQ scores than patients who did not (p = 0.04). No significant difference was found between BPAQ scores of patients respectively being administered mood stabilizers (including valproate), antidepressant, and the patients who were not. These results were found independently of socio-demographical variables, psychotic symptomatology, insight, compliance into treatment, daily-administered antipsychotic dose, the way of antipsychotic administration (oral vs long acting), current alcohol disorder and daily cannabis consumption. The results of the present study are in favor of a superior efficacy of second-generation antipsychotics in aggressiveness in patients with schizophrenia, but these results need further investigation in longitudinal studies. Given the potent side effects of benzodiazepines (especially dependency and cognitive impairment) and the results of the present study, their long-term prescription is not recommended in patients with schizophrenia and aggressive behavior.