OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders of childhood and adolescence. About 30% of patients do not respond to stimulants or cannot tolerate their side effects. Thus, alternative medication, like herbal medicine, should be considered. The aim of this trial is to compare the safety and efficacy of Crocus sativus (saffron) versus methylphenidate in improving symptoms of children with ADHD. METHODS: In a 6-week randomized double-blind study, 54 patients (children 6-17 years old) with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of ADHD were randomly assigned to receive either 20-30 mg/d (20 mg/d for <30 kg and 30 mg/d for >30 kg) methylphenidate (MPH) or 20-30 mg/d saffron capsules depending on weight (20 mg/d for <30 kg and 30 mg/d for >30 kg). Symptoms were assessed using the Teacher and Parent Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) at baseline and weeks 3 and 6. RESULTS: Fifty patients completed the trial. General linear model repeated measures showed no significant difference between the two groups on Parent and Teacher Rating Scale scores (F = 0.749, df = 1.317, p = 0.425, and F = 0.249, df = 1.410, p = 0.701, respectively). Changes in Teacher and Parent ADHD Rating Scale scores from baseline to the study end were not significantly different between the saffron group and the MPH group (p = 0.731 and p = 0.883, respectively). The frequency of adverse effects was similar between saffron and MPH groups. CONCLUSION: Short-term therapy with saffron capsule showed the same efficacy compared with methylphenidate. Nevertheless, larger controlled studies with longer treatment periods are necessary for future studies.