AIM: To compare the efficacy of different administration regimens of compound tropicamide eyedrops (CTE) for pupil dilation for children with dark iris. METHODS: A prospective, comparative, randomized interventional study was conducted. Children in Group 1 received CTE 3 times with a 3min interval between each application. Children in Group 2 received CTE 4 times with a 5min interval between each application. We measured their pupil diameters at baseline (pre-drug instillation) and 30min and 60min post-drug instillation and assessed the pupillary light reflex at 60min post-drug instillation. RESULTS: In total, 194 eyes of 101 children were enrolled. The changes of pupil diameter at 30min and 60min post-drug instillation were 1.2±0.6 mm and 2.3±1.0 mm in Group 1, and 2.3±0.9 mm and 3.7±1.0 mm in Group 2, respectively. Group 2 showed a larger change in pupil size than Group 1 at 30min (P<0.01) and 60min (P<0.01). The effect of pupil dilation in Group 2 was 1.25 times that in Group 1. The change in pupil size was positively associated with age. A higher proportion of children in Group 1 had smaller pupil diameter and reactive pupils at the final time point, with only 33 children (33.7%) had final pupil size ≥6.5 mm, and only 9 children (9.2%) had non-reactive pupils. Children in Group 2 achieved larger pupil diameter and more non-reactive pupils at the final time point, with 84 children (87.5%) had final pupil size ≥6.5 mm, and only 22 children (22.9%) had reactive pupils. CONCLUSION: Increasing the frequency of compound tropicamide and lengthening the interval between eye drop applications can produce stronger mydriatic effects.