PURPOSE: To determine the effect of intraocular gas tamponade on drug levels achieved with the intravitreal sustained-release fluocinolone (FL)/5-fluorouracil (5-FU) codrug pellet. METHODS: After insertion of a 10-mg codrug pellet into the right eyes of 43 New Zealand white rabbits, perfluoropropane (0.4 mL of 100% C3F8) or a control sham was then injected into the midvitreous cavity. On postoperative days 2, 4, 7, 21, and 42, aqueous samples were collected, the rabbits were killed, and the right eyes were enucleated. The vitreous and remaining codrug pellet were then isolated. Pellet and intravitreal drug levels were determined by high-pressure liquid chromatography. RESULTS: No measurable drug levels were detected in any of the aqueous samples. Maximal gas expansion occurred by day 4 and partial resorption was observed by days 14 to 21. Vitreous FL and 5-FU levels during C3F8 expansion (day 2) were statistically significantly higher in the gas-filled eyes. On postoperative days 4, 7, 21, and 42, there were no statistically significant differences between FL and 5-FU drug levels in eyes containing C3F8 as compared with control eyes. Pellet codrug, FL, and 5-FU levels over time were similar in gas-filled and control eyes. CONCLUSIONS: Intraocular gas tamponade does not significantly affect the sustained intravitreal drug levels achieved with the FL/5-FU codrug. If clinically efficacious, the FL/5-FU codrug formulation does not need to be altered to treat proliferative vitreoretinopathy in the presence of intraocular gas.