Objective To investigate the impact of paroxetine（ Par） on the compositions of sphingomyelin（ SM） and ceramide（ Cer） in prefrontal cortex（ PFC） of rats with chronic unpredictable stress （CUS）. Methods A total of 21 SD rats were randomly divided into control group（ Sham）， model group（ CUS） and paroxetine group（ Par）， with 7 rats in each group. CUS group and Par group received CUS and then received intraperitoneal injection of normal saline（ 1 ml/kg） or paroxetine（ 10 mg/kg） for 7 consecutive days； rats in Sham group only received intraperitoneal injection of normal saline at the same time. Then rats were killed and the PFC was isolated for lipomics analysis. The relative concentrations of total SM and Cer as well as the different small molecules in the PFC of each group were compared. Results The relative abundance multiple of SM in CUS group was（ 0.73±0.16）， which was significantly lower than that in Sham group（ 1.02±0.08） and Par group（ 0.89±0.05）（ all P＜0.05）； the relative abundance multiple of Cer in CUS group was（ 1.35±0.18）， which was significantly higher than that in Sham group（ 1.05±0.10） and Par group（ 1.14±0.11）（ all P＜0.05）； there was no significant difference in the relative abundance of SM and Cer between Sham and Par group （P ＞ 0.05）. Compared with Sham group， the relative abundances of 5 SM and 2 Cer molecules in CUS group were decreased， while the relative abundances of 1 SM and 5 Cer molecules were increased（ all P＜0.05）. Compared with Par group， the relative abundances of 2 SM molecules were decreased and 8 Cer molecules were increased in CUS group（ all P＜0.05）. The relative abundances of 1 SM and 2 Cer molecules were decreased and the relative abundances of 1 SM and 6 Cer molecules were in creased in Sham group （all P ＜ 0.05）.Conclusions The level of SM was decreased while the level of Cer was increased in prefrontal cortex of CUS model rats， which can be improved by paroxetine intervention.