There is an expectation that ocular inserts, regardless of the nature of the polymer, will faithfully reduce systemic drug absorption. This may not necessarily be so, however, since not all polymers would release drug at the same rate and to the same extent. The objective of the present study was to determine how drug release rate from various polymeric ocular inserts may influence systemic timolol absorption in the pigmented rabbit. The inserts tested were made of polyvinyl alcohol (PVA), hydroxypropylcellulose (HPC), or partial ethyl ester of poly(vinyl methyl ether/maleic anhydride) (PVMMA), approximately 89.4% w/w in all cases. Some polyvinyl alcohol inserts contained timolol in salt form with Carbopol 940 (PVA-C940), 8.6% w/w. The time course of timolol in plasma over 6 hr was monitored using reversed phase HPLC. While all inserts reduced the peak timolol concentration in plasma (Cmax), only the PVA and HPC inserts, which released timolol rapidly in vitro, reduced the extent of systemic timolol absorption (AUC). On the other hand, both PVA-C940 and PVMMA inserts, which released timolol relatively slowly in vitro, increased the extent of systemic timolol absorption. Moreover, the time at which peak timolol concentration was achieved in the plasma was much delayed, raising the possibility of delayed timolol absorption until discharge of the presumably viscous and/or mucoadhesive solutions of PVA-C940 and PVMMA inserts into the nasal cavity. It may be concluded that not all polymeric ocular inserts reduce systemic timolol absorption. Whether an insert would do so depends on the interplay of residence time in the conjunctival sac and rate of drug release from the insert.