The use of both prescription and illicit drugs creates the potential for drug interactions as a function of both pharmacokinetic and pharmacodynamic processes. One such interaction is that of fluoxetine and methylenedioxymethamphetamine (MDMA) in which fluoxetine attenuates the positive-like effects of MDMA. The present work extends the analysis of their interaction by examining the impact of fluoxetine on the aversive effects of MDMA which in balance with its rewarding effects may mediate its abuse potential. Male and female Sprague–Dawley rats were given fluoxetine (10 mg/kg every 4th day for five injections) prior to taste avoidance training with MDMA (3.2 mg/kg). MDMA induced taste avoidance in males and females (faster acquisition in females). Fluoxetine preexposure attenuated this avoidance in males, but not females. For males, the attenuation was partial as MDMA-conditioned animals with fluoxetine preexposure still displayed a significant reduction in fluid intake compared to controls. Consistent with prior work assessing the interaction of fluoxetine and MDMA, fluoxetine preexposure impacted the ability of MDMA to support taste avoidance learning, specifically attenuating the aversive effect of the drug. Prior work has shown that fluoxetine attenuates MDMA’s positive effects which might lead to reduced intake of the drug; however, the concurrent reduction in the drug’s aversive effects may still shift the overall affective balance of these two affective properties toward continued use and abuse. The fact that the attenuation was only evident in males needs further study to investigate the sex-dependent effects of drug history.