Neuropsychological change after 6weeks of clozapine treatment was examined in 18 treatment-refractory patients to test anticipated domain-specific cognitive improvements. The first aim of this study was to test the assumption that increased homogeneity of sample and treatment would yield an experimental design with sufficient sensitivity to detect general intellectual changes with clozapine that were not apparent in one previous investigation. The second aim was to test predictions derived from a domain-specific review of all other investigations with clozapine suggesting salient gains on tests sensitive to motor and mental speed, visual spatial manipulation, and new learning of verbal material. The results showed that the comprehensive neuropsychological test battery was sensitive to general cognitive changes with clozapine, and supported the hypothesized domain-specific gains on tests of motor and mental speed, visual spatial manipulation and new verbal learning. Novel gains were also apparent on tests of new learning with nonverbal material. The results are discussed in relation to aspects of experimental design necessary for the evaluation of prospective medication-induced changes in cognitive skill, particularly in future investigations designed to differentiate between second-generation antipsychotic medications.