Medulloblastoma and neuroblastoma belong to a group of neoplasms designated as primitive neuroectodermal tumors (PNETs). Secreted protein, acidic and rich in cysteine (SPARC) is a matrix-associated glycoprotein that influences a variety of cellular activities in vitro and in vivo. In this study, we provide evidence that expression of SPARC cDNA induces autophagy in PNET cells followed by apoptotic cell death. SPARC-induced autophagy was morphologically characterized by (i) the formation of membrane-bound autophagic vacuoles (AVOs), (ii) increase in the levels of microtubule-associated protein light chain 3 (LC3) and (iii) induction of the lysososmal enzyme cathepsin B. Cathepsin B, in turn induced mitochondrial release of cytochrome c and activated caspase-3, events that signify the onset of apoptotic cell death. In agreement with these observations, inhibition of autophagy by 3-MA reduced AVO formation and LC3 and inhibited apoptosis, suggesting that autophagy has a role in SPARC-mediated apoptosis. Blocking cathepsin B expression with a specific inhibitor of cathepsin B suppressed apoptosis but did not affect autophagy, which suggests that cathepsin B is a molecular link between autophagy and apoptosis. In summary, these findings show that SPARC expression induces autophagy, which results in the elevation of cathepsin B and subsequent mitochondria-mediated apoptosis.