BACKGROUND: Major depressive disorder (MDD) accompanied by anxious distress is a chronic and disabling disorder. Its conventional drug therapies often have low patient compliance due to drug-related side effects. In Persian medicine, lavender-dodder syrup is one formula often recommended for such disorders. OBJECTIVE: This study compares the effects of lavender-dodder syrup to the standard drug, citalopram, for treating MDD with anxious distress. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: This six-week, double-blind, randomized, clinical trial was carried out in a psychiatric outpatient clinic. During the six-week intervention period, patients in citalopram group received citalopram tablets 20 mg/d plus 5 mL placebo syrup every 12 h; patients in group B received placebo tablets once daily plus 5 mL of lavender-dodder herbal syrup every 12 h. MAIN OUTCOME MEASURES: Primary outcome measures, depression and anxiety, were evaluated using the Hamilton Depression/Anxiety Rating Scales, and were scored at the beginning of the study and at weeks three and six. Secondary outcome measures including response to treatment and remission rates were also compared between the two groups. RESULTS: Fifty-six participants with MDD and anxious distress were randomly assigned to two groups. Mean depression scores significantly decreased in citalopram and herbal groups at weeks three and six (time effect: P < 0.001), although the observed changes were not significantly different between the groups (intervention effect: P = 0.61). Mean anxiety scores were not significantly different between the two groups at week three (P = 0.75). However, at the end of week six, the observed decrease was significantly higher in the herbal syrup group than the citalopram group (intervention effect: P = 0.007). CONCLUSION: The herbal syrup is an effective and tolerable supplement for treating MDD with anxious distress. TRIAL REGISTRATION NUMBER IRCT2016102430459N1 on Iranian Registry of Clinical Trials.