Of the antioxidant vitamin E isoforms, α-tocopherol (αT) and γ-tocopherol (γT) are the most abundant in the human diet, and αT is consumed from both natural and synthetic sources. αT and γT may differentially impact inflammation and influence cardiovascular outcomes, in part by modulating gene expression. The goal of this study was to compare the effects of natural αT, synthetic αT, and γT on gene expression in two human cell lines. Human aortic smooth muscle cells (HASMC) and endothelial cells (HAEC) were either: (1) treated with 25 μM tocopherolsalone, or (2) pretreated with tocopherols prior to a pro-inflammatory cytokine (tumor necrosis factor-alpha, TNF-α) stimulation. The expression of atherosclerosis-related genes was measured using RT2 Profiler PCR arrays. Tocopherol treatments alone did not significantly modulate the expression of genes in unstimulated HASMC or HAEC. TNF-α stimulation significantly upregulated genes involved with apoptosis and stress response in both cell lines. Pretreating cells with tocopherols did not normalize the gene expression changes induced by TNF-α. However, αT pretreatments, but not γT pretreatments, attenuated TNF expression in both HASMC and HAEC. These findings suggest that under stimulated conditions, αT modestly modulates the expression of selective genes and that αT may be more anti-inflammatory than γT.