Objective To detect serum level changes of CCHE1 and TCF21 in coronary artery disease (CAD) patients and to explore their clinical significances. Patients and Methods. A total of 150 CAD patients were divided into the mild lesion group (n = 52), moderate lesion group (n = 48), and severe lesion group (n = 50), respectively, according to the Gensini score. In addition, they were divided into single vessel lesion (n = 42), two vessel lesions (n = 49), and three vessel lesions group (n = 59), respectively. Serum levels of CCHE1 and TCF21 in CAD patients were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Spearman's rank correlation was conducted to assess the relationship between levels of CCHE1 and TCF21 and severity and numbers of vessel lesions in CAD. Pearson's correlation test was used for analyzing the correlation between CCHE1 and TCF21 levels. A multivariable logistic regression test was performed to evaluate the influences of CCHE1 and TCF21 levels on CAD severity and the occurrence of cardiovascular events within 3 years of follow-up. Results Significant differences in incidences of diabetes and hypertension were identified in CAD patients divided according to CAD severity. In addition, significant differences in incidences of drinking, diabetes, and hypertension were identified in CAD patients divided according to numbers of vessel lesions. The serum level of CCHE1 was positively related to CAD severity and numbers of vessel lesions, while TCF21 displayed a negative relationship. During the 3-year follow-up, the incidence of cardiovascular events was 39.3% (59/150). CAD severity, numbers of vessel lesions, and serum levels of CCHE1 and TCF21 were independent factors influencing the occurrence of cardiovascular events in CAD patients. Conclusions The increased serum level of CCHE1 and decreased TCF21 level are closely related to CAD severity, which are able to influence the prognosis in CAD patients.