Aim To explore the impact of pioglitazone on calcification of rat vascular smooth muscle cells in vitro through the pathway of apoptosis induced by endoplasmic reticulum stress, and its signal transduction and molecular mechanisms. Methods Beta glycerin joint sodium pyruvate sodium phosphate was used to prepare calcified vascular smooth muscle cell model, with different concentrations （10, 50, 100 μmol/L） pyrazole ketone of wide intervention. Cell calcification was observed by using Von Kossa staining and alizarin red S staining, and calcium was determined by alkaline phosphatase （ALP）activity. Flow cytometry and Tunel method were used to detect apoptosis rate, real time fluorescence quantitative RT-PCR and Western Blot method were used to detect mRNA and protein expression of glucose regulated protein 78 （GRP78）, cysteine-containing aspartate-specific proteases-12 （Caspase-12） and Runt-related transcription factor 2 （Runx2） in each group. Results The calcium content, ALP activity in calcification group increased compared with normal cells （P<0.05）, and different concentrations of pioglitazone dose dependently reduced the calcium content and the activity of ALP in the calcification of vascular smooth muscle cells in rats （P<0.05） The apoptosis rate of calcification group was obviously higher than that in control group, and different concentration of pioglitazone dose dependently reduced apoptosis rate of vascular smooth muscle cell（P<0.05） mRNA and protein expression of GRP78, caspase-12 and Runx2 increased significantly in calcification group, and different concentration of pioglitazone dose dependently downregulated mRNA and protein expression of GRP78, caspase-12 and Runx2 of vascular smooth muscle cell in rat （P<0.05）. Conclusion Pioglitazone can reduce calcification of vascular smooth muscle cells induced by beta glycerol phosphate through the pathways of apoptosis induced by endoplasmic reticulum stress, which effect may be related to GRP78, caspase-12 and Runx2 expression downgrade.