Background: The loss of retinal pericytes is one of the earliest changes associated with diabetic retinopathy (DR). Chronic hyperglycemia induces apoptosis of these cells, leading to the onset and progression of DR. In this study, we investigated the effects of Homonoia riparia (H. riparia) and its major component, myricitrin, on high glucose (HG)-induced apoptosis of primary human retinal pericytes (HRPs). Methods: The effects of an ethanol extract of H. riparia leaves and of myricitrin on HRP viability and apoptosis were investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry. Reactive oxygen species (ROS) levels were measured using 2′,7′-dichlorofluorescein diacetate. The activity of specificity protein 1 (Sp1), a transcription factor, was measured using a luciferase reporter assay and western blot analyses were performed to measure the expression of proteins involved in signaling and apoptosis. Results: HG produced cytotoxic effects on HRPs, which showed increased Sp1 expression and ROS levels. H. riparia extract and myricitrin significantly inhibited HG-induced apoptosis and ROS generation, and also inhibited Sp1 activity. This was evidenced by an attenuation of the HG-mediated increase in extracellular signal-regulated kinase phosphorylation. Conclusion: These data indicate that HG-mediated induction of Sp1 is one of a number of key signaling pathways involved in HRP apoptosis, and that H. riparia extracts or myricitrin may provide useful approaches to preventing and treating DR.