Cardiovascular disease is more common in schizophrenia patients than in the general population, with a hypothesized contribution from increases in adiposity produced by antipsychotic medications. We sought to test the relationship between adiposity and insulin resistance using frequently sampled intravenous glucose tolerance tests (FSIVGTTs) to quantify whole-body insulin sensitivity in chronically treated patients with schizophrenia or schizoaffective disorder and untreated healthy controls. FSIVGTTs, body mass index (BMI), and waist circumference were obtained in nondiabetic patients (n=63) receiving olanzapine, risperidone, ziprasidone, or first generation antipsychotics, as well as in healthy controls (n=14). Subject groups (including untreated healthy controls) were matched for BMI and all treated patient groups were additionally matched for age. Bergman's minimal model (MinMod) was used to calculate insulin sensitivity (S(I)), as well as secondary measures of interest. BMI and waist circumference significantly predicted insulin sensitivity measured as MinMod S(I) (F(1,62)=35.11, p<0.0001 and F(1,46)=24.48, p<0.0001, respectively). In addition, BMI and waist circumference significantly predicted the acute plasma insulin response to the glucose challenge (AIR(G)), consistent with a beta cell compensatory response to insulin resistance (MinMod AIR(G) F(1,65)=22.42, p<0.0001 and F(1,49)=11.72, p=0.0013, respectively). Adiposity levels occurring during antipsychotic treatment are strongly related to insulin resistance, confirming that antipsychotic-induced weight gain can contribute to increased cardiometabolic risk in this population.