Objectives: To compare the effects of nitrous oxide and midazolam on cognition and mood. Design: A three-way, counterbalanced, cross-over study, using patients receiving conscious sedation for routine dental treatment. Methods: On each of three separate visits, patients performed a computerised test battery to determine baseline cognitive performance. Then, following administration of either midazolam, nitrous oxide, or no drug, patients re-performed the test battery. Finally, patients completed visual analogue scales assessing their subjective mood state. Results: Relative to baseline performance, midazolam administration produced significantly slower reaction times compared with nitrous oxide and no-drug conditions. Furthermore, patients receiving midazolam were impaired in accuracy relative to the other conditions on many of the cognitive tasks, particularly those assessing the recall of information. Patient performance in nitrous oxide and control conditions did not significantly differ. These results could not be explained by differences in mood between the conditions, as subjective mood ratings during midazolam or nitrous oxide administration were very similar. Conclusions: It is important for clinicians to be aware that peri-operative recall of information is reduced in patients who have undergone midazolam sedation. This is an advantage for patients who are anxious, and do not wish to be aware of the operative treatment being performed. However, as the cognitive impairment is enduring, an adult escort and written post-operative instructions should be mandatory for midazolam sedation patients. In contrast, the use of nitrous oxide sedation does not significantly impair higher cognitive tasks and thus patients receiving nitrous oxide sedation can resume normal activities in the post-operative period.