Hydroxypropyl methylcellulose (HPMC), an inert polymer that forms a viscoelastic solution in aqueous media, is useful for anterior segment surgery. A 2.2% solution of HPMC (MW 86,000 daltons) of 6,000 centistokes viscosity was evaluated as a vitreous substitute in rabbit eyes. Four days after perfluoropropane gas compression of the vitreous, the gas was exchanged with 0.5 ml HPMC. The aqueous was removed 1 and 2 weeks postinjection and at sacrifice, the vitreous was removed at sacrifice. HPMC concentrations in aqueous humor were: 0 hr, 0%; 48 hr, 0.002%; 1 week, 0.004%; 2 weeks, 0.001%; 4 weeks, 0%. HPMC concentrations in vitreous were: 48 hr, 93% of amount injected; 2 weeks, 88%; 4 weeks, 78%; 10 weeks, 0%. Hyaluronidase injected in the vitreous enhanced HPMC elimination. The effect of HPMC also was assayed on a cultured retinal pigment epithelial monolayer. Compared with controls, HPMC-treated cells maintained normal morphology at 5 days, and 2, 3, and 4 weeks as observed by light microscopy. Because of rapid intraocular decrease in viscosity, HPMC is not a good long-term vitreous replacement to support retinal tears. However, HPMC might be useful short-term to avoid postoperative hypotony, and to remove intraocular silicone oil and peel retinal membranes.