Hyperglycemia-induced oxidative stress is a key mediator of renal tubular hypertrophy in diabetic nephropathy (DN). The molecular mechanisms of antioxidants responsible for inhibition of renal tubular hypertrophy in DN are incompletely characterized. We now aim at verifying the effects of N-acetylcysteine (NAC) and taurine on cellular hypertrophy in renal tubular epithelial cells, under high ambient glucose. We found that NAC and taurine treatments significantly attenuated high glucose (HG)-inhibited cellular growth and HG-induced hypertrophy. HG-induced Raf-1, p42/p44 mitogen-activated protein kinase (MAPK), Janus kinase 2 (JAK2), signal transducers and activators of transcription 1 (STAT1) and STAT3 (but not STAT5) activation were markedly blocked by NAC and taurine. Moreover, NAC and taurine increased cyclin D1/cdk4 activation and suppressed p21^Waf1/Cip1 and p27^Kip1 expression in HG-treated cells. It seems that apoptosis was not observed in these treatments. There were no changes in bcl-2 and poly(ADP-ribose) polymerase (PARP) expression, and mitochondrial cytochrome c release. However, NAC or taurine markedly inhibited the stimulation by HG of fibronectin and type IV collagen protein levels. It is concluded that both NAC and taurine significantly attenuated HG-induced activation of the Raf-1/MAPK and the JAK2-STAT1/STAT3 signaling pathways and hypertrophic growth in renal tubular epithelial cells.