Quetiapine is an effective atypical antipsychotic medication that was reported to reduce substance use and craving in patients with schizophrenia. This clinical effect of quetiapine is hypothesized to be due to its low affinity for dopamine receptors and its weak attenuation of central reward functions. The present study was designed to determine the magnitude of the reward attenuation induced by different doses of quetiapine and its effectiveness at reducing the effect of cocaine. Experiments were performed on male Sprague-Dawley rats that were trained to produce operant responses to receive rewarding stimulations to the medial forebrain bundle. In a first study, we tested the effects of three doses of quetiapine (5, 10, 20 mg/kg) on brain stimulation reward using a within-subject design and the curve-shift method. In a second study, we tested the effectiveness of a low and high dose of quetiapine (5 and 20 mg/kg) at blocking the reward enhancing effect of cocaine (4 mg/kg) in different groups of animals. Quetiapine produced a weak (20%) but significant attenuation of reward. Cocaine enhanced reward by 20% and the combination of cocaine with the high dose of quetiapine lead to cancellation of each drug effect. The low dose of quetiapine did not alter baseline reward but completely blocked the effect of cocaine. The magnitude of the reward attenuation induced by quetiapine is consistent with its low affinity for dopamine receptors. Its actions on dopamine and non-dopamine neurotransmission are likely to account for its effectiveness at blocking the enhancement of reward by cocaine.