Accumulating evidence has revealed that obstructive sleep apnea (OSA) and high homocysteine (Hcy) levels play important roles in the increased risk of hypertension and cardiovascular disease. We investigated whether the presence of elevated Hcy levels among individuals with OSA increase the risk of hypertension in a cohort study. A total of 1825 participants were selected from the cohort study. A high homocysteine level (Hcy) was defined as those in the 75th percentile of Hcy levels of the study cohort. The prevalence of hypertension was higher among subjects with OSA and high Hcy levels than among the other groups stratified by the presence of OSA and high Hcy levels. The incidence of hypertension at 6-year follow-up was: Hcy[-]/OSA[-] vs. Hcy[+]/OSA[-] vs. Hcy[-]/OSA[+] vs. Hcy[+]/OSA[+], 14.2% vs. 19.8% vs. 24.2% vs. 36.1%. After adjusting for confounding factors, subjects with OSA and high Hcy levels had a 1.86-fold risk of developing hypertension compared to those without OSA and high Hcy levels. Moderate to severe OSA group with the highest tertile of Hcy levels had a 2.31-fold increased risk of developing hypertension. Interaction between Hcy and OSA on development of hypertension was significant, suggesting that these conditions may constitute an important determinant.