Hyperhomocysteinemia (HHcy) has been observed to promote hypertension, but the mechanisms are unclear. Toll-like receptor 4 (TLR-4) is a cellular membrane protein that is ubiquitously expressed in all cell types of the vasculature. TLR-4 activation has been known to promote inflammation that has been associated with pathogenesis of hypertension. In this study, we hypothesize that HHcy induces hypertension by TLR-4 activation that promotes inflammatory cytokine up-regulation (IL-1β, IL-6, TNF-α) and initiation of mitochondria- dependent apoptosis leading to cell death and chronic vascular inflammation. To test the hypothesis, we used C57BL/6J mice (WT); Cystathionine-β-synthase deficient mice (CBS+/-) with genetic mild HHcy; C3H/HeJ (C3H) mice, with TLR-4 mutation and mice with combined genetic HHcy and TLR-4 mutation (CBS+/-/C3H). Ultrasonography of the superior mesenteric artery (SMA) detected an increase in wall-to-lumen ratio, resistive index (RI) and pulsatility index (PI). The tail cuff blood pressure (BP) measurement revealed elevated blood pressure in CBS+/- mice. The RI, PI and wall-to-lumen ratio of the SMA in CBS+/-/C3H mice were similar to the control group and blood pressure was significantly alleviated. The expression of TLR-4, IL-1β, IL-6 and TNF-α was up regulated in the SMA tissue of CBS+/- mice group and reduced in CBS+/-/C3H group. CBS+/- mice exhibited an up regulation of molecules (BAX, caspase-9, caspase-3) involved in mitochondria- mediated cell death pathway that were attenuated in CBS+/-/C3H mice group. We conclude that HHcy promotes TLR-4- driven chronic vascular inflammation and mitochondria- mediated cell death inducing hypertension. TLR-4 mutation attenuates vascular inflammation and cell death that suppresses hypertension.