Atypical antipsychotic (AAP) medications that have revolutionized the treatment of mental illness have become stigmatized by metabolic side effects, including obesity and diabetes. It remains controversial whether the defects are treatment induced or disease related. Although the mechanisms underlying these metabolic defects are not understood, it is assumed that the initiating pathophysiology is weight gain, secondary to centrally mediated increases in appetite. To determine if the AAPs have detrimental metabolic effects independent of weight gain or psychiatric disease, we administered olanzapine, aripiprazole, or placebo for 9 days to healthy subjects (n = 10, each group) under controlled in-patient conditions while maintaining activity levels. Prior to and after the interventions, we conducted a meal challenge and a euglycemic-hyperinsulinemic clamp to evaluate insulin sensitivity and glucose disposal. We found that olanzapine, an AAP highly associated with weight gain, causes significant elevations in postprandial insulin, glucagon-like peptide 1 (GLP-1), and glucagon coincident with insulin resistance compared with placebo. Aripiprazole, an AAP considered metabolically sparing, induces insulin resistance but has no effect on postprandial hormones. Importantly, the metabolic changes occur in the absence of weight gain, increases in food intake and hunger, or psychiatric disease, suggesting that AAPs exert direct effects on tissues independent of mechanisms regulating eating behavior.