Major depression affects the central nervous system and thereafter the autonomic nervous system, immune system, and endocrine system. Na+/K+ ATPase, as a major mediator of cellular transmembrane ionic gradients, plays an important role in nervous signal transduction. Three types of Na+/K+ ATPase alpha subunit isoforms (ATP1A1, ATP1A2, and ATP1A3) are found in brain but vary in the type of cell and level of expression. It has been confirmed that reduced expression of ATP1A2 and ATP1A3 are related to depressive disorder. However, there is no reported correlation between ATP1A1 and major depression. This study investigated the potential correlation between ATP1A1 gene expression level and major depression. The expression levels of ATP1A1 gene in the peripheral circulation of both depressive patients and healthy human controls were quantified by using reverse transcripted quantitative polymerase chain reaction. Statistical analysis showed a significant decrease of ATP1A1 expression level in major depression patients when compared to that of healthy controls (P < 0.01). The differences of gene nucleotide sequences and protein structures among ATP1A1, ATP1A2, and ATP1A3 were also illustrated. This study demonstrates, for the first time, that ATP1A1 gene expression level is significantly associated with major depression and suggests that ATP1A1 could be a significant molecular marker for diagnosis.