It was recently found that age-related changes in SMP30 expression can be modulated by antioxidative action. In the current study, the modulation of SMP30 gene expression was explored by (a) antioxidative calorie restriction (CR), (b) proinflammatory lipopolysaccharide (LPS), in aged rat, (c) oxidative stress promoter, tert-butylhydroperoxide (t-BHP)-injected mouse, and (d) t-BHP-treated Ac2F cells. Utilizing EMSA, particular attention was given to the binding activity of unidentified transcription factor in sites 3 and 5 that are located in -800 bp of the SMP30 promoter. Results showed that CR prevented the age-related decrease in SMP30 expression, and also showed that SMP30 gene expression and binding activities of sites 3 and 5 decreased with treatments of t-BHP or LPS. These findings were confirmed by the antioxidant NAC and ERK-specific inhibitor PD098059 that blunted decreased SMP30 gene expression and binding activity of sites 3 and 5 by t-BHP in Ac2F cell system. Our data strongly indicate that the SMP30 transcriptional process is redox-sensitive and its modulation occurs at DNA binding sites 3 and 5 in the promoter region. Perhaps a more significant finding of the present study is that the downregulation of SMP30 is likely involved in ERK signal pathway.