Objective To evaluate the safety of new-generation of antidepressants and amitriptyline in the treatment of depression in patients with coronary heart disease (CHD). Methods A total of 194 patients with first-episode depression with CHD were divided into amitriptyline group(n=40), venlafaxine group(n=40), mirtazapine group(n=48)and escitalo?pram group(n=66). The blood routine test, liver function, blood lipids and blood glucose (GLU) were monitored after treat?ment for six weeks, and which were compared before and after treatment. Results The levels of white blood cells (WBC) and neutrophil count (NE) were significantly lower in amitriptyline group after 6-week treatment (P<0.05), but the levels of acid alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (T-CHO) and GLU were significant?ly increased after treatment than those before treatment (P<0.05). The levels of WBC, NE and GLU were significantly de?creased in venlafaxine group after 6-week treatment (P<0.05). The levels of ALT, AST, low density lipoprotein (LDL) were significantly increased in mirtazapine group after six-week treatment (P<0.05). In escitalopram group, the level of three ac?yl glycerin (TG) was significantly increased after six-week treatment than before treatment ( P<0.05). There was a signifi?cant difference in AST change after treatment between venlafaxine group and mirtazapine group (P<0.05). There was a sig?nificant decrease in WBC in amitriptyline group than that of mirtazapine group after six-week treatment ( P<0.05). There was a significant decrease in NE in amitriptyline group than that of mirtazapine group and escitalopram group ( P<0.05). The increase level of AST was significant higher in amitriptyline group than that of venlafaxine group (P < 0.05). Conclusion Three different kinds of new-generation of antidepressants have fewer influence in routine blood test, liver function, blood lipids and blood glucose than those of amitriptyline in the treatment of depression in patients with CHD.