Both apoptosis and caspase-3 activity in adipose tissue-derived stem cells play an important role in the therapeutic process of diabetes patients. The purpose of this study was to investigate the effect of advanced glycation end products-human serum albumin (AGE-HSA) on apoptosis in human adipose tissue-derived stem cells (ADSCs) and to characterize the signal transduction pathways activated by AGEs that are involved in apoptosis regulation. AGE-HSA promoted apoptosis and caspase-3 activity in ADSCs. However, the effects of AGE-HSA were significantly attenuated by an inhibitor of p38 MAPK, but not by inhibitors of JNK MAPK or ERK MAPK. AGE-HSA also upregulated the expression of RAGE. Silencing of the RAGE gene inhibited AGE-HSA-induced apoptosis, and activation and expression of phosphorylated p38 MAPK. These results suggest that AGE-HSA promote the apoptosis of ADSCs in vitro via a RAGE-dependent p38 MAPK pathway.