In neurons, hypoxia activates intracellular death‐related pathways, yet the antiapoptotic mechanisms triggered by hypoxia remain unclear. In RN46A neuronal cells, minimum media growth conditions induced cell death as early as 12 h after the cells were placed in these conditions (i.e., after removal of B‐27 supplement). However, apoptosis occurred in hypoxia (1% O₂) only after 48 h, and in fact hypoxia reduced the apoptosis associated with trophic factor withdrawal. Furthermore, hypoxia induced time‐dependent increases in expression of platelet‐derived growth factor (PDGF) B mRNA and protein, as well as PDGF‐β receptor phosphorylation. Although exogenous PDGF‐BB induced only transient Akt activation, hypoxia triggered persistent activation of Akt for up to 24 h. Inhibition of phosphatidylinositol 3‐kinase (PI3K) or of PDGF‐β receptor phosphorylation abrogated both hypoxia‐induced and exogenous PDGF‐BB‐induced Akt phosphorylation, and it completely abolished hypoxia‐induced protection from media supplement deprivation, which suggests that the long‐lasting activation of Akt during hypoxia and the prosurvival induction were due to endogenously generated PDGF‐BB. Furthermore, these inhibitors decreased hypoxia‐inducible factor 1α (HIF‐1α) DNA binding, which suggests that the PDGF/PDGF‐β receptor/Akt pathway induces downstream HIF‐1α gene transcription. We conclude that in RN46A neuronal cells, hypoxia activates an autocrine‐paracrine antiapoptotic mechanism that involves up‐regulation of PDGF‐B and PDGF‐β receptor‐dependent activation of the PI3K/Akt signaling pathway to induce downstream transcription of survival genes.