Objective To determine whether fluoxetine, a commonly used selective serotonin reuptake inhibitors (SSRIs), could exacerbate bleeding in a intracerebral hemorrhage (ICH) mouse model. Methods Forty two 12-14 month old female specific pathogen free C57BL/6 mice were selected. Mice were randomly divided into fluoxetine group (fluoxetine pre-treatment) and control group, with 21 mice in each group. After treated with fluoxetine for 7 days, ICH was induced by injecting collagenase Ⅶ-S into the right striatum of middle-aged female mice. Effects of fluoxetine on exacerbating bleeding were evaluated by a combination of histologic, molecular, cellular, and behavioral assessments. Results On the third day after ICH, the hemorrhage volumes of the control group and fluoxetine group were (4.59±1.80) mm3 and (6.09±1.08) mm3, respectively. In middle-aged female mice subjected to collagenase-induced ICH, fluoxetine pre-treatment significantly exacerbated neurological deficit, cerebral hemorrhage volume, myelin damage, hemoglobin and iron deposition, neuronal degeneration, and brain edema (P<0.05). Although there was no significant difference in tail bleeding time between the two groups, fluoxetine pre-treatment might increase tail bleeding time [(276.73±211.06) vs. (438.00±236.79) s; t=−1.686, P=0.055]. Conclusions The use of fluoxetine and more generally of SSRIs, which inhibits platelet aggregation, may exacerbate bleeding after ICH. Thus, patients with depression after ICH may avoid concomitant use of such drugs when choosing an antidepressant.