Glutamatergic N-methyl-d-aspartate (NMDA) receptor hypofunction has been proposed as a mechanism underlying psychosis. d-cycloserine, a partial agonist at the glycine site of the NMDA receptor, enhances learning in animal models, although tachyphylaxis develops with repeated dosing. Once-weekly dosing of d-cycloserine produces persistent improvement when combined with cognitive behavioral therapy (CBT) in anxiety disorders. Delusional beliefs can be conceptualized as a learning deficit, characterized by the failure to use contradictory evidence to modify the belief. CBT techniques have been developed with modest success to facilitate such reality-testing (or new learning) in delusional beliefs. The current study evaluated whether d-cycloserine could potentiate beneficial effects of CBT on delusional severity. Twenty-one outpatients with schizophrenia or schizoaffective disorder and moderately severe delusions were randomized in a double-blind cross-over design to receive a single-dose of either d-cycloserine 50mg or placebo in a counterbalanced order on two consecutive weeks 1h prior to a CBT intervention involving training in the generation of alternative beliefs. Assessments were completed at baseline, 7days following the first study drug administration and 7days following the second study drug administration. Contrary to prediction, there was no significant d-cycloserine treatment effect on delusional distress or severity as measured by the SAPS or PSYRATS. An unexpected finding was an order effect, whereby subjects who received d-cycloserine first had significantly reduced delusional severity, distress, and belief conviction on PSYRATS compared to subjects who received placebo first. However, this finding is consistent with animal models in which d-cycloserine enhances learning only when accompanying the first exposure to training.