Isolated systolic hypertension (ISH) is characterized by increased arterial stiffness (Wallace, et al, 2007). The mechanisms underlying arterial stiffness and subsequently ISH in human are not fully understood. Several factors have been demonstrated to be involved in arterial stiffness such as the liver-produced anti-classificatory hormone, fetuin-A, endothelial-derived vasoconstrictor, endothelin-1 (ET-1), and the sex hormones, testosterone and progesterone (Mori, et al, 2007; McEniery, et al, 2007; Dockery, et al, 2002; Natoli, et al, 2005). Changes of blood level of these parameters in ISH and hypertensive patients (both SBP and DBP are high) might reflect the level of their expression and production, therefore contributing to the pathophysiology of these disease statuses, which still not clear. ELISA was used to measure serum level of these parameters in three groups: (I) ISH patients; (II) hypertensive patients and (III) normal subjects. Samples were collected from several hospital in Makkah, Saudi Arabia during the period of 2009 and 2010. The serum level of the parameters is expressed as mean± standard error of the mean. Comparisons between groups was made by using t-test. In ISH, there is decrease in fetuin-A (0.17±0.03; n=39) as compared to normal subjects (P<0.05) and no changes were observed in serum level of testosterone (19.2±1.9; n=15), progesterone (0.72±0.2; n=19) and ET-1 (0.09±0.02; n=30) as compared to normal subjects (P>0.05). In hypertension, there is an increase in ET-1 (0.2±0.03; n=14) and decrease in testosterone (8.125 ±1.8; n=9) as compared to normal subjects (P<0.05) and no changes were observed in fetuin-A (0.29±0.06; n=18) and progesterone (0.67±0.3; n=7) as compared to normal subjects (P>0.05). Low level of the anti-calcification hormones, fetuin-A, in ISH suggest its possible contribution in the arterial stiffness and therefore increase in the SBP in this group of patients. Increase in the potent vasoconstrictor, endothelin-1, and decrease in testosterone in hypertensive patients suggest their possible involvement in the pathophysiology of this vascular disease. These findings open a new understanding of the pathophysiology of ISH and hypertension and bring hope for better treatment of these diseases status.