Blocking dopamine (DA) D(2) receptors is the sine qua non of antipsychotic activity. However, it is this same process that accounts for their liability to produce extrapyramidal symptoms (EPS) and hyperprolactinemia. It remains unclear, though, whether there are other negative consequences that might result from DA D(2) blockade. For example, previous research has demonstrated a robust relationship between DA and both cognition and mood. The present study was designed to evaluate the impact of DA D(2) antagonism on each of these domains. Healthy participants (N = 59) were randomized to receive a single oral dose of 1, 3 or 5 mg of haloperidol or placebo. Participants were tested on cognitive and mood measures at baseline, 4 and 24 h post-administration of medication. In terms of cognition, the greatest negative impact was on sustained attention, reaction time and speed of information processing, with the effect on sustained attention reaching statistical significance. For mood, the greatest negative impact occurred on measures of contentment, anger and confusion, with the effect on contentment reaching statistical significance. Global effects for both cognition and mood domains were greatest at 4 h post-administration of haloperidol and dose-dependent. The present results suggest that DA D(2) blockade, as induced by haloperidol, produces important deficits that extend beyond motor or endocrine changes.