Accumulating evidence suggests that C-type lectin-like receptor-2 (CLEC-2) plays an important role in atherothrombosis. In this case-control study, we investigated the association between CLEC-2 and incidence of coronary artery disease (CAD). A total of 216 patients, including 14 cases of stable angina pectoris (SAP, non-ACS) and 202 cases of acute coronary syndrome (ACS), and 89 non-CAD control subjects were enrolled. Plasma levels of soluble CLEC-2 (sCLEC-2) were measured using the enzyme-linked immunosorbent assay (ELISA). Compared with the control group (65.69 (55.36-143.22) pg/mL), the plasma levels of sCLEC-2 were significantly increased in patients with CAD (133.67 (88.76-220.09) pg/mL) and ACS (134.16 (88.88-225.81) pg/mL). The multivariate adjusted odds ratios (95% confidence interval) of CAD reached 2.01 (1.52-2.66) (Ptrend < 0.001) for each 1-quartile increase in sCLEC-2. Restricted cubic splines showed a positive dose-response association between sCLEC2 and CAD incidence (Plinearity < 0.001). The addition of sCLEC-2 to conventional risk factors improved the C statistic (0.821 vs. 0.761, P = 0.004) and reclassification ability (net reclassification improvement: 57.45%, P < 0.001; integrated discrimination improvement: 8.27%, P < 0.001) for CAD. In conclusion, high plasma sCLEC-2 is independently associated with CAD risk, and the prognostic value of sCLEC-2 may be evaluated in future prospective studies.