The purpose of this study was to compare the efficacy of the exposure and response prevention (ERP) and fluoxetine in obsessive-compulsive patients. 45 patients with obsessive-compulsive disorder (OCD) were randomly assigned to 3 groups: exposure and response prevention, fluoxetine and waiting-list. All groups were matched by variables such as age, sex, level of education and marital status. To gather the data, a battery of instruments including Moudsley Obsessive-Compulsive Inventory (MOCI), Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI) was used. All patients completed the questionnaires in 3 stages (pre test, post test, and follow-up with 2 month intervals). The findings indicated that the ERP therapy was more effective than fluoxetine to reduce the OCD severity only in short-term (P<0.05). This difference between ERP and waiting list groups was significant in short-term and long-term too (P<0.01). The difference between fluoxetine and waiting-list groups was significant only in short-term (P<0.05). The efficacy of fluoxetine on depression severity in short-term and long-term was more significant than ERP and waiting-list groups (P<0.01, P<0.05, respectively). The efficacy ofERP and fluoxetine on the anxiety severity was not significant.