Age-related macular degeneration (AMD) is a slowly progressing multifactorial disease involving genetic abnormalities and environmental insults. Genetic studies have demonstrated that polymorphisms in different complement proteins increase the risk for developing AMD. Previously, we have shown that in retinal pigment epithelium (RPE) monolayers, exposure to oxidative stress reduced complement inhibition on the cell surface, with the resulting increase in complement activation leading to vascular endothelial growth factor (VEGF) release and VEGF-receptor-2-mediated disruption of the monolayer barrier function. Complement activation was found to be sublytic and transient and require the assembly of the membrane attack complex (MAC). Here, we asked how this transient, sublytic complement activation could trigger long-term pathological changes in RPE cells. The initial activation of the L-type voltage-gated calcium channels was followed by calcium influx and activation of several kinases. While Erk/Ras activation was found to be transient, Src kinase phosphorylation was sustained. We have shown previously that Src kinase controls VEGF release from RPE cells by altering the activity of the L-type channel. We propose that the prolonged Src kinase activation, and its resulting effects on membrane depolarization and calcium influx, leads to sustained VEGF secretion. In addition, the previously shown effect of the autocrine positive feedback loop in RPE cells, involving VEGF-induced VEGF production and secretion via VEGFR-2 receptors, will augment and prolong the effects of sublytic complement activation. In summary, identification of the links between oxidative stress, chronic, low-grade activation of the complement system, and elevated VEGF expression and secretion might offer opportunities to selectively inhibit pathological VEGF release only.