We were interested in gaining further insight into the potential of targeting PI3K/Akt signaling as a novel antiproliferative approach in neuroblastoma. EXPERIMENTAL DESIGN: The expression pattern and functions of class I(A) PI3K isoforms were investigated in tumor samples and cell lines. Effects on cell survival and downstream signaling were analyzed following down-regulation of p110alpha or p110delta in SH-SY5Y and LA-N-1 cells by means of RNA interference. RESULTS: Overexpression of the catalytic p110delta and regulatory p85alpha isoforms was detected in a panel of primary neuroblastoma samples and cell lines, compared with normal adrenal gland tissue. Although down-regulation of either p110alpha or p110delta led to impaired cell growth, reduced expression of p110delta also had a selective effect on the survival of SH-SY5Y cells. Decreased levels of p110delta were found to induce apoptosis and lead to lower expression levels of antiapoptotic Bcl-2 family proteins. SH-SY5Y cells with decreased p110delta levels also displayed reduced activation of ribosomal protein S6 kinase in response to stimulation with epidermal growth factor and insulin-like growth factor-I. CONCLUSIONS: Together, our data reveal a novel function of p110delta in neuroblastoma growth and survival.