Metabolic syndrome's cluster of obesity, high blood sugar, high blood pressure and high cholesterol can lead to heart disease, stroke and diabetes.
The study authors recommend doctors check for metabolic syndrome in patients taking this antipsychotic.
Their work is published in the American Journal of Psychiatry.
Dr Steven Lamberti and his colleagues at the University of Rochester Medical Center studied 93 schizophrenic patients who were taking clozapine and compared them with 2,700 individuals from a health database who were of a similar age, weight and ethnicity.
More than half of the patients taking clozapine had metabolic syndrome compared to only a fifth of the comparison group.
Dr Lamberti said this created a difficult choice for patients and doctors.
He said about one in five people with schizophrenia do not respond to other medications and for them clozapine is the last hope.
People with severe mental illness die, on average 10 years younger
because of physical health problems and are five times more likely to
experience diabetes than the general population.
Paul Corry of Rethink
"It's a very difficult decision. On the one hand, we know that metabolic syndrome is associated with increased morbidity and mortality.
"We think that patients with metabolic syndrome have a two or three fold increased risk of cardiovascular disease. And the prevalence of metabolic syndrome in patients taking clozapine was over twice what it should be.
"On the other hand, patients who have schizophrenia that require clozapine do not respond to other medications and in the absence of this treatment are faced with the possibility of a life of active psychosis."
He stressed that people with schizophrenia are known to exercise less and have poorer diets and that these factors also contribute to metabolic syndrome.
People with schizophrenia who are not taking any medication have also been shown to be at higher risk of diabetes.
"We do not know why. There are a number of theories. It might be that what ever is affecting the brain in schizophrenia is also affecting the metabolic system."
He also said that newer, atypical antipsychotic medications, such as clozapine, have shown advantages over the older medications for schizophrenia in terms of both safety and efficacy.
Paul Corry, of Rethink, welcomed the call for practitioners to closely monitor the side effects of medications prescribed to patients.
He added: "People with severe mental illness die, on average 10 years younger because of physical health problems and are five times more likely to experience diabetes than the general population.
"It is crucial that the physical health needs of people with severe mental illness are taken seriously."