〔Abstract〕 Objective To investigate the effects and molecular mechanisms of histone deacetylase(HDAC) inhibitors on the regulation of FKBP3 in esophageal cancer cells ECA109 and KYSE30. Methods Esophageal cancer cells ECA109 and KYSE30 were treated with HDAC inhibitors for 48 h and then harvested and checked for the protein and mRNA levels of FKBP3 by Western blot and qPCR, respectively. HDACs siRNA knockdown experiments were conducted in ECA109 cells and then the expression of FKBP3 were checked. The STRIING database was used to obtain the interaction network between FKBP3 and HDACs. Results The broad-spectrum HDAC inhibitor Vorinostat, and specific HDAC inhibitor Entinostat which targets HDAC1 and HDAC3, both showed inhibitory effects on FKBP3 not only on protein level but also on mRNA level. The specific knockdown of HDAC1 or HDAC2 also led to decreased expression of FKBP3, whereas knockdown of HDAC3 had no such effect. The database indicated that FKBP3 interacted with HDAC1 and HDAC2 and might form a complex to perform biological functions. Conclusion In esophageal cancer cells, HDAC inhibitors can inhibit the expression of FKBP3, which is likely to be achieved by inhibiting HDAC1 and HDAC2.