Objective: The main purpose is to investigate the effect and mechanism of sodium valprate on the transcriptional expression of the human orosomucoid 1-like protein3(ORMDL3). Methods: The effect of sodium valprate on the mRNA expression of ORMDL3 was determined by using semi-quantitative RT-PCR. The effect of sodium valprate on ORMDL3 promoter activity and its mechanism were detected by point mutations and Dual-Luciferase reporter assays. Results: By adding sodium valprate(final concentration of 2 mmol/L) in human embryonic kidney 293 cells (HEK293 cells), it can significantly reduce the expression amount of the human ORMDL3 gene. The luciferase analysis showed that sodium valprate can significantly inhibit the promoter activity of ORMDL3 gene. P300 and CREB binding to the promoter region can drive the ORMDL3 transcription. When sodium valprate act on the plasmids without the binding region of p300 or CREB, there was no significant difference compared with the wild-type plasmid. Conclusion: Sodium valprate can reduce the mRNA level of the human ORMDL3 in HEK293 cells independently of binding with the p300 and CREB in core promoter area of ORMDL3 gene.