VEGF-A is an autocrine survival factor for podocytes, which express two VEGF receptors, VEGF-R1 and VEGF-R3. As VEGF-A is not a known ligand for VEGF-R3, the aim of this investigation was to examine whether VEGF-C, a known ligand for VEGF-R3, served a function in podocyte biology and whether this was VEGF-R3 dependent. VEGF-C protein expression was localised to podocytes in contrast to VEGF-D, which was expressed in parietal epithelial cells. Intracellular calcium ([Ca²⁺]_i) experiments demonstrated that VEGF-C induced a 0.74±0.09 fold reduction in [Ca²⁺]_i compared to baseline in human Conditionally Immortalised Podocytes (hCIPs) (p<0.05, one sample t-test, n=8). Cytotoxicity experiments revealed that in hCIPs VEGF-C reduced cytotoxicity to 81.4±1.9% of serum starved conditions (p<0.001, paired t-test, n=16), similar to VEGF-A (82.8±4.5% of serum starved conditions, p<0.05, paired t-test). MAZ51 (VEGF-R3 kinase inhibitor) inhibited the VEGF-C induced reduction in cytotoxicity (106.2±2.1% of serum starved conditions), whereas MAZ51 by itself had no cytotoxic effects on hCIPs. VEGF-C was also shown to induce a 0.5±0.13 fold reduction in levels of MAPK phosphorylation compared to VEGF-A and VEGF-A-Mab treatment (p<0.05, ANOVA, n=4), yet had no effect on Akt phosphorylation. Surprisingly, immunoprecipitation studies detected no VEGF-C induced phosphorylation of VEGF-R3 in hCIPs, but did so in HMVECs. Moreover, SU5416, a tyrosine kinase inhibitor blocked the VEGF-C induced reduction in cytotoxicity (106 ±2.8% of serum starved conditions) at concentrations specific for VEGFR1. Together, these results suggest for the first time that VEGF-C acts in an autocrine manner in cultured podocytes to promote survival, although the receptor or receptor complex activated has yet to be elucidated.