Background Coronary artery calcification (CAC) is a predictor of cardiovascular events and plaque burden and is closely associated with chronic inflammation. Interleukin (IL)-37 is a newly discovered member of the IL-1 family and is considered an anti-inflammatory cytokine. Our recent study on mice indicated that IL-37 could attenuate atherosclerosis and vascular calcification, which suggests that IL-37 could be associated with the development of atherosclerosis and related diseases. The aim of this study was to investigate if IL-37 plays a role in the progression of CAC in patients. Methods Two hundred participants with suspected cardiovascular disease were recruited. The levels of plasma IL-37, osteoprotegerin (OPG), hypersensitive C-reactive protein (hsCRP) together with other biochemical parameters were measured, and a coronary calcium assessment was carried out by multi-detector row CT. A score of < 10 AU (Agatston units) denotes an absence of CAC, a score of 11-100 AU denotes mild CAC, 101-400 denotes moderate CAC, and > 400 AU denotes severe CAC. Results Our initial data showed that there were no apparent differences in plasma IL-37 levels among patients with or without mild or moderate CAC. However, IL-37 levels were significantly increased in patients with severe CAC (P < 0.001). Similar results were observed for plasma OPG and hsCRP levels. When IL-37 levels in patients with severe calcification were compared with that in all of the other non-severe CAC groups, it became apparent that there was a significant positive correlation between IL-37 level and severe CAC (r = 0.360, P < 0.001; OR = 1.033) using Spearman's correlation and binary logistic regression analysis. Conclusions This study demonstrates that the anti-inflammatory cytokine IL-37 is associated with high coronary calcium levels, suggesting that IL-37 expression may be caused by the activation of inflammation and that IL-37 might become a predictor of severe CAC in the future, which requires further investigation.