Cadmium is a toxic heavy metal and an environmental pollutant. Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is a negative regulator of the family of MAPK. In this study, we investigated the effect of heavy metals on MKP-1 expression in C6 rat glioma cells. Cadmium treatment induced MKP-1 at both protein and mRNA levels while cobalt or manganese treatment did not, suggesting the specificity. Cadmium treatment also depleted intracellular GSH and activated p38 MAPK, JNKs, and AKT. Profoundly, pretreatment with thiol-containing compounds NAC or GSH, but not vitamin E, blocked GSH depletion, 38 MAPK activation and MKP-1 expression by cadmium. Moreover, pharmacological inhibition of p38 MAPK by SB203580 suppressed the cadmium-induced MKP-1. Collectively, these results demonstrate that cadmium specifically induces MKP-1 by transcriptional up-regulation in C6 cells in a mechanism associated with the glutathione depletion-dependent p38 MAPK activation.