Obsessive-compulsive disorder (OCD) is an anxiety disorder which can substantially disable children's ability to function at home and school. Clinicians frequently rely on knowledge about symptoms that can be examined early in treatment to determine future treatment effectiveness. However, OCD in preschoolers has also received little attention in literature. To the best of our knowledge, there is only one retrospective chart review and one case report in the literature for preschool cases treated with SSRIs. Therefore, the effect of fluoxetine on preschool children was imprecisely understood. The aim of this case report was to examine the efficacy and safety of fluoxetine treatment for pediatric OCD. Four preschool children with OCD completed an 8-week fluoxetine (up to 20 mg) trial. We diagnosed OCD according to Diagnostic and statistical manual of mental disorders, 4th edition, text revision (DSM-IV-TR) criteria and symptoms of OCD were assessed with the Childrens' Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Initial and post-treatment symptom severity and improvement were assessed by using the severity (S) and improvement (I) scales of Clinical Global Impressions Scale (CGI). The CY-BOCS total, obsessions and compulsions subscale scores and CGI-S scores were significantly improved for all of the cases at the end of the eighth week. In this case report four preschool children, with severe OCD and resistant to the previous non-psychopharmacologic treatment responded well to fluoxetine monotherapy. On the other hand, the usage of SSRIs in preschool children remains highly controversial, due to the lack of data on safety and efficacy.