The cellular prion protein PrP^C is a ubiquitous plasma membrane-anchored glycoprotein, predominantly expressed in the central nervous system. Recent researches have proved that PrP^C is up-regulated in several cancer forms and sustains the multidrug resistance phenotypes. Since it exhibits a high binding affinity toward copper (Cu) ions, the authors questioned if prion protein overexpression in cancer cells may be a compensatory response to an altered Cu homeostasis. To this aim, a rat (B104) and a human (SHSY-5Y) neuroblastoma cell lines have been selected as experimental models and PrP^C levels significantly depressed in both cell lines by enzymatic and molecular biology (RNA interference technology) methods. The absolute Cu uptake activity was then quantified by a fluorimetric technique. The PrP^C-dependent component of Cu transport activity was also analyzed in 48 h Cu deprived B104 cells, to explore a possible involvement of this protein in pathological events. Knock-down of PrP^C levels in SHSY-5Y cells suppressed the uptake of Cu by up to about 50%. Accordingly, the enzymatic cleavage of prion proteins from B104 cell surface resulted in 30% loss of Cu transport activity. When B104 cells were subjected to 48 h Cu starvation, a heavy increase of PrP^C expression was observed, accounting for about 50% surplus of ion uptake. Results suggest a role for PrP^C as a Cu import protein and support the hypothesis that a disrupted metal homeostasis may sustain cancer progression.