Small interfering RNAs (siRNAs) are a proven therapeutic approach for controlling gene expression in the liver. Expanding the clinical potential of RNA interference (RNAi) requires developing strategies to enhance delivery to extra-hepatic tissues. In this study we examine inhibitingtransthyretin(TRR) gene expression by short interfering RNAs (siRNAs) in the eye. Anti-TTRsiRNAs have been developed as successful drugs to treat TTR amyloidosis. When administered systemically, anti-TTRsiRNAs alleviate symptoms by blockingTTRexpression in the liver. However, TTR amyloidosis also affects the eye, suggesting a need for reducing ocularTTRgene expression. Here, we demonstrate that C5 and 2’-O-linked lipid-modified siRNAs formulated in saline can inhibitTTRexpression in the eye when administered locally by intravitreal (IVT) injection. Modeling suggests that length and accessibility of the lipid chains contributes toin vivosilencing. GalNAc modified anti-dsRNAs also inhibitTTRexpression, albeit less potently. These data support lipid modified siRNAs as an approach to treating the ocular consequences of TTR amyloidosis. Inhibition ofTTRexpression throughout the eye demonstrates that lipid-siRNA conjugates have the potential to be a versatile platform for ocular drug discovery.