Previous studies suggested that the senescence of bone marrow mesenchymal stem cells (BM-MSCs) played an important role in the pathological process of systemic lupus erythematosus (SLE). However, the molecular mechanisms that govern this phenomenon have not been fully elucidated. Recent studies reported the activation of endoplasmic reticulum stress (ERS) participated in the growth arrest in G1 phase of cell cycle. In this study, we aimed to investigate whether ERS would induce the senescence of BM-MSCs from SLE patients. We found that there was increased expression of Glucose Regulated Protein 78 (GRP 78) in BM-MSCs from SLE patients, which indicated the activation of ERS in BM-MSCs from SLE patients. Accumulation of p27 was also found in BM-MSCs from SLE patients. Interestingly, as a chemical chaperone helping the correct folding of proteins, 4-phenylbutyric acid (4-PBA) partly rescued the senescence of BM-MSCs from SLE patients and alleviated the level of p27. These results implicated ERS-mediated senescence as a critical determinant of BM-MSCs from SLE patients.