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Antipsychotic (AP) treatment, in particular with some second-generation drugs, is associated with weight gain and other metabolic side effects. However, the relationship between drug-induced weight gain and dyslipidemia is not well understood. We investigated how cardiometabolic risk factors were related to body mass during treatment with different APs under real-life conditions.This cross-sectional naturalistic study included 242 subjects with severe mental disorders who were on monotherapy with olanzapine (OLZ) or clozapine (CLZ) (n = 80), monotherapy with other APs (n = 80), or unmedicated (n = 82). Groups were adjusted for age and compared for prevalence of the metabolic syndrome and its components. Groups were further adjusted for body mass and compared for mean values of blood pressure, lipids, and fasting glucose.There was no significant intergroup difference in the prevalence of metabolic syndrome, obesity, hypertension, or hyperglycemia. Despite similar body mass index, OLZ/CLZ-treated subjects had significantly higher prevalence of dyslipidemia (high triglyceride and low HDL cholesterol levels) than unmedicated subjects. They also had higher mean values of triglycerides (P = 0.003) and lower mean values of HDL cholesterol (P < 0.001). Patients treated with other APs had intermediate values.Intergroup differences in body mass index were minimal in this naturalistic setting, probably because of awareness of this treatment hazard among clinicians. However, independently of body mass, dyslipidemia was significantly associated with AP treatment, in particular with OLZ and CLZ. These findings indicate a primary effect of APs on lipid regulation, important in understanding their mechanism of action, and with clinical implications.