Cardiovascular disease and atherothrombosis account for the majority of deaths worldwide. Plaque rupture, thrombus formation, and vessel occlusion contribute to the acute clinical manifestations of atherothrombosis. Previously we have shown that the unfolded protein response (UPR) has an important role in monocyte-macrophage differentiation. Furthermore, macrophage infiltration, lipid accumulation and foam cell formation are key events in atherogenesis. Endoplasmic reticulum (ER) stress-dependent apoptosis also contributes to atherosclerotic lesion growth and plaque necrosis. The aim of the current study was to examine whether 4-phenylbutyrate (4-PBA), a small chemical chaperone that alleviates ER stress, confers protection against atherosclerosis when provided via drinking water. To investigate the ability of 4-PBA to affect atherosclerotic lesion growth, at 12 weeks of age female ApoE-/- mice on chow diet were provided with 4-PBA (1 - 2.5 g/kg/d) in their drinking water for five weeks, ad libitum. Following treatment, mice were sacrificed, their tissues collected and atherosclerotic lesions examined by immunohistochemistry. Early atherosclerotic lesion area was significantly reduced in ApoE-/- mice provided 4-PBA-treated water from 12 - 17 weeks of age, relative to controls (0.6 x105 ± 0.1 μm2 versus 1.1 x105 ± 0.1 μm2, respectively, P < 0.05). We hypothesized that 4-PBA drinking water decreased lesion size by a mechanism involving reduced ER stress and monocyte-macrophage differentiation. In support of this mechanism, preliminary data indicates 4-PBA inhibited monocyte-macrophage differentiation, as measured by mRNA expression of the macrophage marker MSR-1 (0.5 ± 0.2 fold-change vs. control) and cell adherence (37 ± 5% vs. control) in PMA-treated THP-1 cells. In summary, these findings provide evidence that 4-PBA-treated drinking water reduced atherosclerotic lesion size in a mouse model of atherosclerosis. We hypothesize that 4-PBA acts in part through its ability to reduce ER stress and modulate monocyte/macrophage differentiation and function. Additional studies are in progress to further examine the mechanisms by which 4-PBA affects atherogenesis.