Depression is commonly present in patients with coronary heart disease (CHD). Identification of early predictors of depression in CHD patients is an important direction of current research in the field of psychosomatic medicine. Serotonin transporter gene polymorphism (5-HTTLPR) was earlier reported to contribute to the development of depression comorbid to CHD. The present study aimed at investigating the role of the 5-HTTLPR polymorphism, stress factors and personality traits in the prediction of depressive symptoms in patients with CHD. The study included 169 male patients, aged from 31 to 84 years, mean age 59±8.8 years. Depression was diagnosed in 135 (79.9%) patients; in 71 (42%) patients it was related to the presence of CHD (nosogenic factor). Severity of depressive symptoms as defined by HAM-D-21 was associated with the interaction between the 5-HTTLPR polymorphism, nosogenic factor and trait anxiety. Risk of depression was 7.0 times higher in carriers of an S allele in the presence of the nosogenic factor. In other combinations of a 5-HTTLPR variant with the presence or absence of the nosogenic factor, trait anxiety contributed significantly to the variance of depressive symptoms. Patients with higher scores on the Spilberger STAI had 5 and 7 times higher risk of moderate and marked depression compared to those with moderate and low anxiety scores. The approach suggested in the study may be useful for the prediction of depression and its severity in patients with CHD.