Hypodopaminergic and hyponoradrenergic pathophysiology may be a basis for primary and/or secondary negative symptoms in schizophrenia. The hypothesis that enhanced neurotransmission in these systems would be therapeutic for negative symptoms was tested by comparing mazindol and placebo in a double-blind, cross-over design trial. Outcome following mazindol supplementation was comparable to placebo supplementation (F(1,30) = 0.9; p = .57). Results for deficit and non-deficit schizophrenia subjects were similar, and were not affected by whether concurrent the antipsychotic drug treatment was clozapine, fluphenazine, or haloperidol. The efficacy hypothesis was not supported for either primary or secondary negative symptoms.