The aim of the present study was to clarify the mechanism underlying the inhibition of cell proliferation in human lung cancer A549 cells by selenium (Se) compounds. Methylseleninic acid (CH₃SeO₂H, abbreviated as MSA), a synthetic Se compound, is a direct precursor of active methylselenol (CH₃SeH) and is considered to be one of beneficial agents for cancer prevention and therapy. Sodium selenite (Na₂SeO₃), an inorganic Se form, is utilized in clinical Se supplementation. MSA markedly inhibited the growth of A549 cells at a concentration of 2.5×10⁻⁶ mol/L for 1 d. On Day 1, Na₂SeO₃ also inhibited A549 cell growth at the concentration of 7.5×10⁻⁶ mol/L. These compounds induced cell cycle arrest at the G₁ phase and apoptosis under the inhibitory condition. Reduced glutathione (GSH) is critical to MSA or Na₂SeO₃ metabolism. The depletion of intracellular GSH suppressed Na₂SeO₃-induced G₁ arrest, but promoted Na₂SeO₃-induced apoptosis. Therefore, Na₂SeO₃ appears to have directly induced apoptosis. In contrast, the MSA-induced G₁ arrest was ameliorated by a marked decrease in GSH content. Additionally, the depletion of GSH slightly suppressed MSA-induced apoptosis. The difference in inhibitory effects between MSA and Na₂SeO₃ may be due to this variation in GSH-related metabolism. After exposure of A549 cells to MSA, the GSH content was significantly decreased. These results indicate that because MSA-induced G₁ arrest and apoptosis induction are enhanced by GSH, the maintenance of GSH is essential for the effective anticancer action of MSA in A549 cells.