Human glomerular mesangial cells (HMCs) have a finite lifespan and eventually enter irreversible growth arrest known as cellular senescence which is thought to contribute to kidney aging and age-related kidney disorders, such as chronic kidney disease. The signal transducer and activator of transcription 1 (STAT1) is a latent transcription factor involved in a variety of signal transduction pathways, including cell proliferation, apoptosis, and differentiation, but whether it could regulate HMCs senescence still remains to be explored. In our study, induction of Angiotensin II (Ang II) and H(2)O(2) accelerated premature senescence of HMCs as confirmed by increased senescence-associated -β-galactosidase (SA-β-gal) positive staining cells and G0/G1 cell cycle arrest. The STAT1 and STAT3 activity and the expression of p53 and p21(Cip1) were increased after Angiotensin II and H(2)O(2) treatment. Knockdown STAT1 using RNA interference significantly attenuated the progression of HMCs senescence, decreased the elevated p53 and p21(Cip1), more interestingly, STAT3 and its activity was further enhanced while STAT1 was silenced. Our results indicate that STAT1 might mediate Ang II and H(2)O(2)-induced HMCs senescence through p53/p21(Cip1) pathway and the relative abundance of STAT1 and STAT3.