Timolol eyedrops may cause systemic side-effects in glaucoma patients due to absorption of the drug into systemic circulation. In a previous study, timolol concentrations in plasma were reduced if timolol was administered in ocular inserts instead of eyedrops. We compared the intraocular pressure lowering effect and systemic absorption of timolol inserts to those of 0.5% timolol eyedrops in humans. Inserts of silicone tubing released 90.3 +/- 13.9 micrograms of timolol in 24 hours in vivo. Timolol inserts afforded similar decreases in intraocular pressure in open-angle glaucoma patients as did b.i.d. eyedrops, but produced lower peak timolol concentrations in plasma, 0.70 +/- 0.10 ng/ml and 0.24 +/- 0.05 ng/ml, respectively. After eyedrops, peak concentrations were achieved at 15.0 +/- 2.2 min, while application of an insert resulted in a delayed peak (tmax = 623 +/- 195 min). The insert resulted in a higher systemically absorbed fraction of the timolol dose than the eyedrop, but the peak timolol concentration and daily absorbed amount of timolol were decreased. The release rate of timolol from the inserts in vivo was only slightly less than that in vitro. Silicone devices are useful for clinical testing of controlled delivery properties of ocular drugs.