Objective To evaluate the therapeutic effect of 4-phenylbutyric acid(4-PBA) on endoplasmic reticulum stress of type 2 diabetic (T2DM) rats. Methods To establish a T2DM model in SD rats with injection of low doses streptozotocin(STZ) after being fed with high-fat diets. Ten T2DM rats were treated with 4-PBA for 20 days. The free fatty acids(FFA), insulin and blood glucose were observed by the radioimmunological method.The pathological changes of pancreatic islet were detected by aldehyde fuchsin staining. The level of mRNA of the endoplasmic reticulum stress associated molecules (Caspase-3, GRP78, CHOP) was tested by RT-PCR. Results The concentration of FFA increased significantly in T2DM group ( EM>n/EM>＝8)and high-fat diets group( n＝10) compared with control group( EM>n/EM>＝10). 4-PBA significantly suppressed FFA caused by high-fat diets( EM>n/EM>＝8). The use of the 4-PBA prevented the decrease of insulin in T2DM group and prevented the increase of blood glucose in T2DM group. Aldehyde fuchsin staining showed that, in the T2DM group, the number of pancreatic islet decreased, the shape of pancreatic islet became unreagular, and vacuoles appeared in cytoplasma. The number of pancreatic islet increased after treatment of 4-PBA. The expression of Caspase-3 and CHOP mRNA in T2DM group significantly increased with those in control group and high-fat diets group. Enhanced expression of Caspase-3 and CHOP was decreased by 4-PBA. Conclusion Our data suggest that chemical chaperone 4-PBA may prevent the development of T2DM associated with the decreased expression of the CH