The ETAP concept (Extracellularly Tumor-Activated Prodrug) is a new approach developed to overcome the lack of selectivity and the side effects responsible for the limited efficacy of chemotherapeutic agents. CPI-0004Na, a doxorubicin (Dox) prototype prodrug of this type, is less toxic than free Dox and showed increased efficacy against subcutaneous human tumor xenografts. The aim of this study was to assess the efficacy of the prodrug vs Dox (given ip) at their maximal tolerated dose (MTD) for this administration schedule (129.3 micromol/kg and 12.93 micromol/kg, respectively) against experimentally induced 3LL-H61 carcinoma lung metastases in mice. Our results indicate that, Dox has no effect on the number of lung metastases while CPI-0004Na induces a 38.3% reduction on average. When considering the effect on the proportion of the lungs' surface covered by metastases, Dox induces a 39% reduction while the prodrug CPI-0004Na is about two fold more active with a 71% decrease.