Cognitive enhancement in patients with schizophrenia is a major treatment priority. Because serotonergic approaches have been suggested as a possible mechanism to enhance cognition and many patients with schizophrenia are treated with selective serotonin reuptake inhibitor antidepressants, we evaluated a serotonin reuptake inhibitor, citalopram, as adjunctive therapy to atypical antipsychotic treatment for its cognitive enhancing effects in schizophrenic patients. Nineteen schizophrenic patients were treated in a randomized, placebo-controlled, crossover-designed 24-week study. In phase 1, subjects were randomized equally to 40 mg of citalopram or placebo and were evaluated prior to initiation of pharmacotherapy and at the end of phase 1 (after 12 weeks of treatment with double-blind agent). At the beginning of phase 2, subjects were crossed over to the other treatment and subsequently assessed after 12 weeks of treatment for symptom severity and cognitive performance. There were no statistically significant differences between citalopram 40 mg/d and placebo treatment on any clinical or cognitive measures. These results indicate that citalopram adjunctive treatment to atypical antipsychotics produces no significant cognitive improvement in patients with schizophrenia. Because the subjects in this study were all treated with atypical antipsychotics, it is possible that the pharmacologic profiles of atypical antipsychotic medications at serotonin receptors may have complicated the effects of citalopram augmentation. Further research on alternative serotonergic approaches to cognitive enhancement in schizophrenia is warranted.