It has been reported that diurnal changes in intraocular pressure (IOP) may be related to the fluctuation of melatonin levels in the eye. In order to test this hypothesis, effects of methysergide, tranylcypromine, and p-chlorophenylalanine (PCPA) on IOP recovery were studied in rabbits infused with hypertonic saline. Methysergide, a serotonin blocker at receptor sites, did not affect IOP recovery, presumably because it did not affect melatonin synthesis. Tranylcypromine, a monoamine oxidase inhibitor which preserves serotonin and eventually increases the level of melatonin in tissues, facilitated IOP recovery. PCPA, known to inhibit serotonin synthesis and to lower the melatonin level in tissues, markedly delayed IOP recovery. These results indicate that a chemical which decreases melatonin content in the eye also lowers the IOP and vice versa. It is suggested that some melatonergic mechanism is involved in the circadian rhythm of IOP.