Background: Elevated homocysteine (Hc) levels have a well-established and clear causal relationship to epithelial damage leading to coronary artery disease. Furthermore, it is strongly associated with other metabolic syndrome variables, such as hypertension, which is correlated with type II diabetes mellitus (T2DM). Studies on T2DM in relation to Hc levels have shown both positive and negative associations. The aim of the present study is to examine the relationship between Hc levels and risk of T2DM in the Lebanese population. Methods: We sought to identify whether Hc associates positively or negatively with diabetes in a case-control study, where 2755 subjects enrolled from patients who had been catheterized for coronary artery diagnosis and treatment. We further sought to identify whether the gene variant MTHFR 667C>T is associated with T2DM, and how Hc and MTHFR 667C>T also impact other correlates of T2DM, including the widely used diuretics in this study population. Results: We found that Hc levels were significantly reduced among subjects with diabetes compared to those without diabetes when adjusted for all potential confounders (OR 0.640; 95% CI [0.44-0.92]; p = 0.0200). The associations between Hc levels and other variates contradicted the result: hypertension associates positively with high Hc levels, and with T2DM. The MTHFR 667C>T only associated significantly with high Hc levels. Conclusion: These results suggest population-specific variations among a range of mechanisms that modulate the association of Hc and T2DM, providing a probe for future studies.