Nasolacrimal occlusion (NLO) and eyelid closure are simple techniques that not only increase the ocular bioavailability of topically applied ocular drugs but also reduce the probability of adverse systemic effects. Each serves to improve the therapeutic index. Subsequent to the application of 0.5% timolol maleate, the effects of NLO and eyelid closure were compared with the effects of no procedures. In this experiment, systemic drug absorption in normal volunteers was reduced more than 60%. Measurements were made by radioimmunoassay of timolol in blood plasma. In addition, the diminution of fluorescein in the anterior chamber was observed for three hours following direct application to the lower cul-de-sac. Results indicate a lower fluorescein concentration and a shorter duration of fluorescence in the absence of either experimental technique. Both NLO and eyelid closure seem to be safe, simple, and effective procedures that could minimize dosage requirements, as well as side effects.