Clozapine has proven to be more effective than typical antipsychotics in treatment-refractory schizophrenic patients, and some evidence suggests that it may be particularly useful in treating the negative symptoms of schizophrenia. However, it is unclear whether this observation reflects improvement in "primary" or "secondary" negative symptoms. We hypothesized that a portion of clozapine's effect on negative symptoms would be related to an improvement in positive (psychotic and disorganization) symptoms, a decrease in extrapyramidal side effects (EPSE), and/or a decrease in depressive symptoms. The remainder of its effect would be related to a direct effect on the neural circuits or pathologic processes responsible for the negative symptoms. Twenty-nine treatment-refractory schizophrenics treated with clozapine for 6 weeks were studied. The core negative symptoms measured by the Scale for the Assessment of Negative Symptoms ([SANS] affective flattening, anhedonia/asociality, avolition/apathy, and alogia) all improved with clozapine treatment. Overall, there was a 31% improvement in negative symptoms, a 32% improvement in psychotic symptoms, and a 35% improvement in disorganization. The improvement in negative symptoms was correlated with improvement in disorganization, but not with improvement in psychotic symptoms, depression, or drug-induced EPSE. Although there was a correlation between improvement in negative symptoms and improvement in disorganization, there was a suggestion that the two are changing in parallel, but are independent of each other. It appears that at least a portion of clozapine's effect on core negative symptoms is mediated through a direct effect on the underlying pathophysiology of schizophrenia associated with negative symptoms.