Human herpesvirus 8 (HHV-8) referred to as Kaposi’s sarcomaassociated herpesvirus (KSHV) is forms of Kaposi’s sarcoma. HHV-8 DNA was detected in dorsal root ganglia of KS patients, cerebrospinal fluid of human immunodeficiency virus-positive patients, and brain biopsy specimens from patients with unexplained encephalitis. The genome of HHV-8 contains 89 ORFs, some ORFs with homologous to cellular genes encode to interfere with host immune system, enzymes of nucleotide metabolism, and growth factors. The kaposin protein derived from ORF K12 has been reported to stimulate cell proliferation. In the study, we investigate protein-protein interaction of HHV-8 ORF K12 with neural cell factors using phage display human brain cDNA library. After six-run biopanning, septin4 that interacted with the kaposin protein has been identified. Co-immunoprecipitation showed the binding interaction of recombinant kaposin protein with septin4 protein. In addition, conforcol immunofluorescence assay demonstrated co-locolization of HHV-8 kaposin protein with septin4 protein in SK-N-SH and TE671 cells. Moreover, caspase3 assay showed that the kaposin protein inhibited septin4-induced apoptosis. NFκB-luciferase and Ap-1-luciferase cis-acting reporters revealed that the kaposin protein activated Ap-1 promoter, being associated with the inhibitory affect on septin4-mediated apoptosis. This study will be helpful for insights into the role of the kaposin protein in the HHV-8 pathogenesis.