Objective To explore the efficacy and safety of escitalopram and sertraline in the treatment of anxiety or depression with somatic symptoms in outpatients of the Department of Cardiology.Methods From August 2018 to April 2019, a total of 100 outpatients with psychological disorders and somatic symptoms in a cardiology setting were randomly divided into escitalopram group and sertraline group, treated with either escitalopram or sertraline for 8 weeks. The clinical symptoms were assessed via the Patient Health Questionnaire-15 (PHQ-15), the Generalized Anxiety Disorder 7-Item (GAD-7) and the Patient Health Questionnaire-9 (PHQ-9) before treatment, and 4 weeks and 8 weeks after treatment. At the 8th week, the Clinical Global Impression-Global Improvement Scale (CGI-GI) and Treatment Emergent Symptom Scale (TESS) were used to evaluate the efficacy and side effects of the treatment.Results The scores of PHQ-15, PHQ-9 and GAD-7 at the 4th and 8th week of the treatment were compared with those before treatment, which exhibited that the scores of PHQ-15 (F = 242.604, P < 0.05), PHQ-9 (F = 136.784, P < 0.05) and GAD-7 (F = 198.537, P < 0.05) were different among the distinct time points, and that the GAD-7 score (F = 6.606, P < 0.05) rather than PHQ-15 (F = 1.207, P > 0.05) and PHQ-9 score (F = 2.016, P > 0.05) was different between the groups. In addition, the change trend of PHQ-9 score (F = 4.013, P < 0.05) and that of GAD-7 score (F =9.774, P < 0.05) instead of that of PHQ-15 score (F =2.400, P > 0.05) were different between the two groups. The CGI-GI score was lower in the escitalopram group relative to sertraline group 8 weeks after the treatment (P < 0.05). However, the rate of all symptoms as assessed via TESS was not different between the two groups 8 weeks after the treatment (P > 0.05), and there was no difference in the rate of withdrawal due to adverse reactions between the groups (P > 0.05).Conclusions Escitalopram and sertraline are both effective and safe in the treatment of outpatients with anxiety or depression complicated with somatic symptoms in a cardiology setting. Nevertheless, escitalopram exhibits even better efficacy relative to sertraline.