The central serotonin (5-HT) system is important in regulating behaviors associated with anxiety and depression. While a fair amount is known about the role of 5-HT1 and 5-HT2 receptor subtypes in regulating these behaviors, much less is known about the involvement of the 5-HT3 receptor, especially with regards to its role in sex differences in behavior. Our goal in the present studies was to examine whether deletion of the 5-HT3 receptor produces different effects in adult male and female mice on performance in three behavioral tests. We examined behavior of male and female mice lacking the 5-HT3 receptor (knock-out or KO) and their wild-type (WT) littermates in the Porsolt forced swim test because of its importance in reliably detecting anti-depressant efficacy. In addition, we examined behavior in the defensive withdrawal test and repeated exposure to an open field because behavior in these two tests provides measures of anxiety. In the Porsolt swim test, sex differences were eliminated by deletion of the 5-HT3 receptor while deletion had no effect in the habituation of locomotor activity to repeated exposure to an open field. In the defensive withdrawal test, deletion of the 5-HT3 receptor had more complex effects though these effects tended to be in the opposite direction in males and females. Together these results suggest that the 5-HT3 receptor regulates behavior-related to depression and anxiety differently in males and females. Whether these effects are due to the interaction of 5-HT3 receptor with gonadal hormones requires further examination.