Abstract: In order to explore the mechanism of response to heavy metal stress of Perinereis aibuhitensis, copper and cadmium were used as stress factors, and transcriptome sequencing technology was used to study the gene expression differences of Perinereis aibuhitensis under the stress of different concentrations of copper (0.01 mg/L, 0.5 mg/L, 1 mg/L) and cadmium (0.005 mg/L, 0.25 mg/L, 0.5 mg/L). The analysis showed that there were 101 differently expressed genes in the six treatment groups, 99 differently expressed genes in the Cu treatment group and 42 differently expressed genes in the Cd treatment group; the differentially expressed genes in the Cu and Cd treatment groups were significantly enriched (P < 0.05) in the glutathione metabolism, peroxisome, Metabolism of xenobiotics by cytochrome P450, and ABC transporter protein pathways. These pathways play an important role in the response to Cu and Cd stresses in the Perinereis aibuhitensis. CYP4f4, CYP1A4, Cyp3a25, CYP2B4, cyp17a1 and Cyp4f14 were screened for resistance genes in response to heavy metal Cu and Cd stresses in this study. The results of this study reveal the effects and differences of Cu and Cd stress on Perinereis aibuhitensis at the genetic level, and provide data support and theoretical reference for the in-depth study of the molecular mechanisms of Perinereis aibuhitensis in response to heavy metal stress and the screening and cloning of resistance genes.