The mydriatic effect of three ocular decongestants, containing 0.1% tetrahydro-zoline hydrochloride, 0.3% chlorpheniramine maleate, and 0.05% tetrahydrozo-line hydrochloride in combination with 0.3% pheniramine maleate, respectively, was evaluated in 10 healthy volunteers. The study was carried out using a single dose of the tested drug, instilling 2 drops in one eye and 2 drops of a placebo in the other. The pupillary diameters were measured by photographic pupillography under basal conditions and 15, 30, 45, 60, 90, and 120 min after each treatment. Near and distance visual acuity and tonometry were evaluated under basal conditions and 50 and 95 min after instillation of drugs. No statistical significant differences between the treated and the control pupil diameters were found after instillation of 0.1% tetrahydrozoline hydrochloride or 0.3% chlorpheniramine maleate. The combination of 0.05% tetrahydrozoline hydrochloride with 0.3% pheniramine maleate caused a significant mydriasis from 30 min up to 120 min (p < 0.01 and p < 0.0005) after instillation, more pronounced in light irides. No local and systemic effects and no effects on visual acuity and ocular pressure were detected. On the basis of our results, it is possible to conclude that the persistent mydriatric action of the two-drug combination is due to a synergism; the use of these eyedrops should be avoided in subjects with narrow-angle glaucoma, light irides, narrow iridocorneal angle, and low anterior chamber for the risk of ocular pressure increase.