OBJECTIVE To test the relationship between serum 25-hydroxyvitamin D[25(OH)D], interleukin-6 (IL-6), and the severity of coronary heart disease (CHD). METHODS A total of 150 patients with suspected myocardial ischemia presenting to our hospital from January 2018 to January 2020 were recruited. All patients underwent percutaneous coronary angiography (CAG). According to CAG results, they were divided into normal group (n=40) and CHD group (n=110). According to the coronary Gensini score, CHD patients were divided into 62 cases in the low-risk group (< 20 points), 31 cases in the moderate-risk group (20-40 points), and 17 cases in the high-risk group (> 40 points). The Gensini scores and serum 25(OH)D and IL-6 levels in each group were recorded, and the correlation between the serum 25(OH)D and IL-6 levels and the severity of the disease was analyzed. The Essen Stroke Risk Scale (ESRS) was evaluated and compared between the two groups. RESULTS The serum 25(OH)D, IL-6 level, and ESRS score in the CHD group and the normal group statistically differed (P < 0.05). In the CHD group, Gensini score, serum IL-6 level and ESRS score increased with the increase of coronary artery stenosis, and 25(OH)D level decreased with the increase of coronary artery stenosis, and all the differences were significant (P < 0.05). Pearson correlation analysis demonstrated that serum IL-6 levels in patients with CHD are positively correlated with the severity of the disease (r=0.724, P < 0.001), and 25(OH)D levels are in a negative relation (r=-0.522, P < 0.001). CONCLUSIONS A decrease of serum 25(OH)D level and increase in IL-6 level in patients with CHD are associated with the severity of CHD. This may provide a reference for clinical diagnosis, treatment, and prognosis.