Purpose: While most studies of fluoxetine have focused on its effects on the cardio/cerebrovascular systems, what is known about its vasomotor effect is still limited. This study was planned to investigate the vasoactive effects of fluoxetine on smooth muscle in rat thoracic aortic rings in an experimental setup. Materials and Methods: 24 adult Wistar albino rats were divided into two groups. Group1-Endothelium intact group, Group2-Endothelium damaged group. Descending thoracic aorta was isolated after cervical dislocation. The aorta rings were immediately placed in organ bath chambers containing Krebs solution. Changes in isometric tension of aorta rings were recorded. Phenylephrine 10-6M was administered and contractions were recorded in groups. Then, fluoxetine was given to Group 1 in cumulative doses (0.01, 0.1, 1, 2 mM). Endothelial damage was created in Group 2. After controlling the endothelial damage by acetylcholine 10-6M, rings were washed for an hour and a second dose of phenylephrine was administered and then fluoxetine was given cumulatively to Group 2 and contractions were recorded. Results: While the dose-dependent main vasodilator effect of fluoxetine was significantly different [F (5.110) =72.740, p<0.001, ηp2=0.77], the dose-group interaction was similar. After 1 mM administration of fluoxetine, less relaxation response occurred in Group 2. Conclusion: The findings suggest that fluoxetine may have beneficial effects such as increasing blood flow on treatment of cardiovascular diseases.