The issue of whether a deletion of the dopamine transporter (DAT) allele (+/- DAT) would differentially alter striatal dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) concentrations and DA release upon potassium and methamphetamine (MA) stimulation between male and female mice was examined. Striatal DA and DOPAC concentrations of female +/- DAT mice were significantly decreased as compared with wild type (+/+) controls and male +/- DAT mice. No such changes were obtained from the olfactory tubercle suggesting that these effects might be specific for the striatum. Potassium-stimulated DA was increased in male and female +/- DAT mice and maximally stimulated DA was obtained from +/- DAT females, although these mice showed the lowest DA concentrations. MA-evoked DA was increased in male and female +/- mice. While MA-evoked DA was significantly increased in +/+ males versus +/+ females, the +/- females showed the highest DA responses, thereby showing a reversal in the results seen in wild-type conditions. These findings indicate: (1) that a deficiency in the DAT interacts with the sex of the subject, (2)+/- DAT females show more extreme changes in dopaminergic responses, and (3) the importance for considering such variables such as sex when examining differences among knock-out conditions.