The overall importance of the peak or the mean serum concentrations as predictors of ocular drug penetration is unknown. To address this fundamental question with an agent which shows promise as adjunctive therapy in the treatment of endophthalmitis, we studied the penetration of ciprofloxacin into the aqueous and vitreous humors following three different modes of systemic administration. New Zealand white rabbits received either a single bolus dose (40 mg kg-1), three intermittent doses of 13.33 mg kg-1 evenly spaced over an 8 hr period, or a continuous infusion of 40 mg kg-1 over an 8 hr period. Pharmacokinetic analysis was performed using RSTRIP II, a non-linear, least square regression model analysis program. The serum area under the concentration-time curve (AUC) values for each mode of drug administration were similar: 32.9 micrograms hr ml-1 for single dose, 31.9 micrograms hr ml-1 for intermittent dose, and 33.8 micrograms hr ml-1 for continuous infusion modes. The percentage penetration into the aqueous and vitreous were also similar; 30.5% and 6.5% for a single dose, 31.6% and 7.4% for intermittent doses and 30.0% and 7.5% for continuous infusion. The penetration into the aqueous and vitreous humors was not influenced by mode of administration. As with other quinolones we have studied, elimination rates were similar for the central and peripheral compartments in the post-distributive phase. Vitreous humor ciprofloxacin concentrations achieved were below that which inhibits most Staphylococcus epidermidis, the most common isolate in patients with post-operative endophthalmitis.