<p>The incidence of hypertension and Type 2 diabetes mellitus (T2DM) is increasing, and their coexistence significantly increases the risk of cardiovascular diseases, stroke, nephropathy, retinopathy, and mortality. Mineralocorticoid receptor activity, primarily regulated by aldosterone, can be beneficially modulated by mineralocorticoid receptor antagonists, especially in patients with mineralocorticoid receptor-associated hypertension, which often occurs with obesity and T2DM. Thus, markers of mineralocorticoid receptor activation, such as 11β-hydroxysteroid dehydrogenase, may help identify patients who may not benefit from standard hypertension treatments. This study investigated the effects of the cortisol-to-cortisone ratio, a marker of 11β-hydroxysteroid dehydrogenase activity, on the relationship between T2DM and hypertension. Using a cross-sectional design, 6931 individuals aged 45–74 years from the Japan Multi-Institutional Collaborative Cohort Study were analyzed. Cortisol and cortisone levels in spot urine samples were measured using liquid chromatography-mass spectrometry. Hypertension (<i>N</i> = 3141) was observed among those who were older; male; current smokers; current drinkers; had T2DM, hyperlipidemia, high BMI; and low perceived stress, physical activity, and eGFR. Multiple logistic regression analysis was performed, and T2DM was associated with hypertension (odds ratio, 1.37; 95% CI, 1.14–1.66). This association varied with cortisol-to-cortisone ratio level and was more evident in participants with a higher odds ratio (2.01; 95% CI, 1.39–2.91; <i>P</i>_interaction = 0.040). These epidemiologic findings suggest that mineralocorticoid receptor activity and 11β-hydroxysteroid dehydrogenase regulation may play a role in hypertension among patients with T2DM, highlighting the potential for targeted treatments based on the cortisol-to-cortisone ratio.</p><p></p>