Under hypoxia, an overexpression of the long HIF-3α2 splice variant resulted in over twofold upregulation of eight genes, including EPO. HIF-3 clearly contributed to EPO signaling as overexpression of HIF-3α2 in two cell lines capable of endogenous EPO production, namely, Hep3B and the SK-N-AS neuroblastoma cell line, and siRNA knockdown of all HIF3A variants in the SK-N-AS cells resulted in significant changes in EPO mRNA and protein levels that are in line with the hypothesis that HIF-3 is a transcription activator. This evidence concerns the gene HIF3A and neuroblastoma.