Abstract Intravitreal injection of drug is commonly used to treat vitreoretinal diseases. In order to assess the effectiveness of the injected drug, it is critical to know the drug distribution within the eye following the injection. This is particularly important when the vitreous medium has been replaced by fluid substitutes. The main objective of this paper is to characterize the spatio-temporal evolution of drug distribution following intravitreal injection into a vitreous substitute such as silicone oil. In addition, water is considered as an intravitreal fluid to represent the liquefaction of vitreous that occurs with aging. Both direct injection of drugs and injection of time-released drugs are studied. The results show that the concentration distribution depends on the properties of the vitreous substitute, the diffusion coefficient of the drug and the permeability of the retinal surface. For drugs with high diffusion coefficients, convection plays a small role in the drug transport. For drugs with low diffusion coefficients and in low viscosity vitreous fluids, convection is seen to play a more important role and can lead to high drug concentrations on the retina which can be potentially toxic. Time-released drug injection is shown to avoid conditions of retinal toxicity, and to provide lower drug concentrations with sustained residence times along the retinal surface. For drugs with high diffusivity and retinal permeability, uniform distribution of the drug is obtained along the surface of the retina, while for drugs with low diffusion coefficient and retinal permeability the concentration of drug is localized along the posterior surface of the retina.