Objective To investigate the impact of fluoxetine on the compositions of phosphatidylethanolamine （PE） in prefrontal cortex（ PFC） of rats with chronic unpredictable stress（ CUS）. Methods A total of 18 SD rats were randomly divided into control group（ Sham）， model group（ CUS） and fluoxetine group（ Flx） by random number table method. CUS group and Flx group received CUS stimulus， and each group received intraperitoneal injection of normal saline（ 1 ml/kg） or fluoxetine（ 10 mg/kg） for 14 consecutive days， while Sham group did not received CUS， but received intraperitoneal injection of normal saline every day. The rats were killed after 14 days and the PFC was isolated for lipomics analysis. The relative concentrations of total PE and different molecules in the PFC of each group were compared. Results （1） Compared to Sham group［ （10.50±7.32）×1011］， the relative concentrations of PE in the CUS group［ （11.95±8.46）×1011］ was significantly reduced（ P＜0.01）， while the difference to Flx group［ （10.31±9.16）×1011］ was not significant（ P＞0.05）.（ 2） Compared to Sham group， the relative concentrations of 3 PE small molecules decreased in CUS group， which are PE（ 36：4p）（ 68.67±14.68）， PE（ 38：3p）（49.73±19.55）， PE（ 38：4p）（76.10±7.84） respectively， with statistical significance（ P＜0.05）. （3） Compared to CUS group， the relative concentrations of 6 PE small molecules decreased in Flx group， which are PE（ 36：4）（72.53±10.22）， PE（ 36：2）（87.86±8.26）， PE（ 38：5p）（75.66±9.53）， PE（ 38：5）（89.93±9.79）， PE（ 38：4）（86.55±15.40）， PE（ 40：7p）（81.57±7.55）respectively， with statistical significance（ P ＜ 0.05）.（ 4） Compared to Sham group， the relative concentrations of 6 PE small molecules decreased in Flx group， which are PE（ 38：4p）（75.85±5.63）， PE（ 38：3p）（44.22±12.61）， PE（ 38：4）（82.49±9.41）， PE（ 40：5p） （78.01±5.31）， PE（ 36：4）（ 76.00±6.34）， PE（ 38：6）（77.45±13.06）， with statistical significance（ P＜0.05）. Conclusions Fluoxetine can regulate the level of PE in prefrontal cortex of CUS model rats.