In this double-blind, placebo-controlled study, we examined the effects of subanaesthetic doses of ketamine (an NMDA glutamate receptor antagonist) and thiopental (a GABA-A receptor agonist) on the event-related potential (ERP) correlates of deviant stimulus processing in 24 healthy adults. Participants completed three separate pharmacological challenge sessions (ketamine, thiopental, saline) in a counterbalanced order. EEG data were recorded both before and during each challenge while participants performed a visual 'oddball' task consisting of infrequent 'target' and 'novel' stimuli intermixed with frequent 'standard' stimuli. We examined drug effects on the amplitude and latency of the P300 (P3) component of the ERP elicited by target (P3b) and novel stimuli (P3a), as well as the N200 (N2) component elicited by both target and novel stimuli, and the N100 (N1) elicited by standard stimuli. Relative to placebo, both drugs reduced the amplitude of parietal P3b. While both drugs reduced parietal P3a and Novelty N2, ketamine also shortened P3a latency, reduced Novelty N2 amplitude more than thiopental, and increased frontal P3a amplitude relative to placebo. Overall, the data suggest that both the GABA-A and NMDA receptor systems modulate P3b and P3a. NMDA antagonism appears to lead to more varied effects on the neural correlates of novelty processing.