We report the case of a patient who was treated with fluoxetine hydrochloride (Prozac) for depression. Approximately 8 weeks into the treatment, an eosinophilic pleural effusion and serum eosinophilia developed. An extensive workup for the etiology of eosinophilic pleural effusion was unrevealing. Pleural biopsy showed a nonspecific inflammatory reaction and mild fibrosis. The pleural effusion and eosinophilia resolved within a few weeks of cessation of the drug. Fluoxetine can be associated with pleural and serum eosinophilia, possibly through an allergic-mediated reaction.