The effects of ondansetron (0.001-0.1 mg/kg) and the novel 5-HT3 receptor antagonist, WAY 100289 (0.01-10.0 mg/kg), on anxiety were examined in male mice using an ethological version of the elevated plus-maze paradigm. This procedure involves scoring specific aspects of defensive behaviour in addition to the more usual spatiotemporal measures. Results show that, at the doses tested, neither compound produced a behavioural profile consistent with anxiety reduction. Indeed, the lowest dose of ondansetron (0.001 mg/kg) produced some behavioural trends more typically associated with mild anxiety enhancement. Data are discussed in relation to the enigmatic effects of 5-HT3 receptor antagonists in animal models of anxiety. It is suggested that the large within- and between-test variability observed with these compounds may indicate an action on mechanisms other than anxiety.