Background: Aortic regurgitation (AR) is a valvulopathy that causes volume overload to the heart leading to left ventricle dilation and eccentric hypertrophy. A common co-morbidity associated with cardiovascular disease is depression. We have previously shown that paroxetine, a selective serotonin re-uptake inhibitor widely prescribed as antidepressant, improves cardiac contractility by preserving fractional shortening (FS) of AR rat hearts.In failing hearts, decrease of the ability of the myocardium to generate an effective shortness velocity is well correlated with the shift of myosin isoform distribution from α to β-MyHC expression. In order to understand the molecular mechanism involved in the improvement of FS after paroxetine treatment, we verified the expression of genes involved in heart contractility and hypertrophy.Methods and Findings: Male Wistar rats were submitted to AR surgery, by retrograde puncture of the aortic valves leaflets, or sham surgery. Morphofunctional variables of the hearts were analyzed by echocardiograms at weeks 4 and 8 after the induction of AR.At week 8 the animals were euthanized for tissue collection and posterior analysis of gene expression by RTq-PCR. Paroxetine treatment for 4 weeks in AR rats reduced the gene expression of β-MyHC and its myomiRs (miR-208 and miR-499). BNP, a molecular biomarker of hypertrophy, also showed their gene expression reduction after paroxetine treatment. Conclusion:These results suggest that paroxetine treatment improves FS in AR hearts through reductions in the expression of several genes involved with cardiac contractility and hypertrophy.